Treatment of Diabetes Mellitus by Long-Acting Formulations of Insulins

ABSTRACT

The application relates to an aqueous pharmaceutical formulation for use in the treatment of Type I or Type II Diabetes Mellitus, wherein the treatment reduces the risk of nocturnal hypoglycemia, said formulation comprising 200-1000 U/mL [equimolar to 200-1000 IU human insulin] of insulin glargine, with the proviso that the concentration of said formulation is not 684 U/mL of insulin glargine.

The application relates to an aqueous pharmaceutical formulation for usein the treatment of Type I or Type II Diabetes Mellitus, wherein thetreatment reduces the risk of nocturnal hypoglycemia, said formulationcomprising 200-1000 U/mL [equimolar to 200-1000 IU human insulin] ofinsulin glargine, with the proviso that the concentration of saidformulation is not 684 U/mL of insulin glargine.

Insulin glargine is 31^(B)-32^(B)-Di-Arg human insulin, an analogue ofhuman insulin, with further substitution of asparagine in position A21by glycine.

WO2008/013938 A2 discloses an aqueous pharmaceutical formulationcomprising insulin glargine at a concentration of 684 U/mL.

Metformin is a biguanide hypoglycemic agent used in the treatment ofnon-insulin-dependent diabetes mellitus (diabetes mellitus type 2) notresponding to dietary modification. Metformin improves glycemic controlby improving insulin sensitivity and decreasing intestinal absorption ofglucose. Metformin is usually administered orally.

Lantus® is an insulin product containing insulin glargine providing 24hour basal insulin supply after single dose subcutaneous injection.

The glucodynamic effect of Lantus® is distinguished from other currentlymarketed insulin products by virtue of a delayed and predictableabsorption of insulin glargine from the subcutaneous injection siteresulting in a smooth, 24 hour time-concentration and action profilewithout a definite peak. Lantus® was developed to meet the medical needfor a long-acting insulin product that can be administered as a singledaily injection to yield normal or near-normal blood glucose controlwith a basal insulin profile that is as smooth as possible over a24-hour period. Such a preparation provides good control of bloodglucose all day, while minimizing the tendency to produce hypoglycemiaseen with other insulin preparations with a more definite “peak” effect.

A considerable number of patients, in particular those with increasedinsulin resistance due to obesity, use large doses to control bloodglucose. For example, a dose of 100 U requires injection of 1 mL Lantus®U100, which may confer some discomfort; each mL Lantus® U100 contains100 U (3.6378 mg) insulin glargine. To reduce the volume of injection, aformulation containing 300 U insulin glargine per mL has been developed.

The purpose of the multicenter, randomized, open-label, parallel-groupstudy as described in Example 1 was to compare the efficacy and safetyof insulin glargine U300 with that of Lantus, both given once-dailysubcutaneous (S.C.) as part of a basal-bolus insulin regimen in patientswith type 2 diabetes. Patients with type 2 diabetes and glycatedhemoglobin A1c (HbA1c) in the range of 7% to 10% injecting at least 42 ULantus U100 or equivalents of neutral protamine Hagedorn (NPH) insulinin a basal plus mealtime insulin regimen were eligible for the study.These patients on relative high doses of basal insulin benefited fromthe lower injection volume of a U300 insulin formulation as comparedwith U100 formulations.

Each mL insulin glargine U300 contains 300 U (10.9134 mg) insulinglargine. This formulation would allow patients to inject the samenumber of units of insulin glargine at one third the volume ofinjection. This formulation is also termed herein as HOE901-U300.

In the study described in Example 1, patients were stratified by theirHbA1c (<8.0%; 8.0%). The primary efficacy analysis testednon-inferiority of insulin glargine U300 compared to Lantus in terms ofchange of HbA1c from baseline to endpoint (scheduled at month 6;non-inferiority margin 0.4% HbA1c units). HbA1c reflects the averageglycemia over several months and has strong predictive value fordiabetes complications. The 6-months duration of study treatment isconsidered to be sufficient for achieving steady state conditions withinsulin glargine U300 after changing over from Lantus or NPH insulinenabling an adequate assessment of time-dependent changes in HbA1c andthe concomitant risk of hypoglycemia.

Main secondary endpoints included nocturnal hypoglycemia. Hypoglycemiais the critical limiting factor in the glycemic management of diabetesin both the short and long term. Despite steady improvements in theglycemic management of diabetes, population-based data indicate thathypoglycemia continues to be a major problem for people with both type 1and type 2 diabetes (American diabetes association, workgroup onhypoglycemia: Defining and Reporting Hypoglycemia in Diabetes. DiabetesCare 28(5), 2005, 1245-1249).

In the study described in Example 1, it was surprisingly found that bytreatment of diabetes type 2 patients with an insulin glargine U300formulation, the risk of a nocturnal hypoglycemic event can besignificantly reduced compared with the treatment with Lantus® U100. Theincidence of patients with at least one nocturnal severe and/orconfirmed hypoglycemia between start of Week 9 and Month 6 was lower inthe U300 group [136/404 (33.7%)] than in the Lantus group [180/400(45.0%)] (see Table 6). Superiority of U300 versus Lantus was shown witha relative risk of 0.75 (95% CI [0.63, 0.89]) (p=0.0010).

Example 2 describes a clinical trial comparing the efficacy and safetyof an insulin glargine U300 (HOE901-U300) formulation and Lantus® U 100,both in combination with oral antihyperglycemic drug(s) in patients withtype 2 Diabetes Mellitus.

In Example 2, non-inferiority of U300 versus Lantus was demonstratedwith the least square mean difference in HbA1c versus Lantus of −0.01%(95% CI [−0.139; 0.119]) (Table 26). The least square mean change inpre-injection SMPG was similar in the U300 (−0.56 mmol/L) and Lantusgroups (−0.51 mmol/L) (Table 28).

Example 2 confirmed that by treatment with an insulin glargine U300formulation, the risk of a nocturnal hypoglycemic event can besignificantly reduced compared with the treatment with Lantus® U100. Ina different patient group, namely type 2 Diabetes Mellitus patients notadequate controlled with antihyperglycemic drug(s) alone, it wassurprisingly found that the incidence of patients with at least onenocturnal severe and/or confirmed hypoglycemia between was lower in theU300 group [87/403 (21.6%)] than in the Lantus group [113/405 (27.9%)](see Table 27). Superiority of U300 versus Lantus was shown with arelative risk of 0.77 (95% CI [0.61, 0.99]) (p=0.0380).

Example 3 compares adaptable dosing intervals with fixed dosingintervals of once-daily administration of an U300 insulin glargineformulation in combination with mealtime insulin. Example 3 is asubstudy of the trial described in example 1. No negative effects wereseen on HbA1c (Table 50) and on fasting plasma glucose (Table 51). Theoverall incidence of hypoglycemia was similar in both regimensregardless of the category of hypoglycemia (Table 53).

Example 6 compares adaptable dosing intervals with fixed dosingintervals of once-daily administration of an U300 insulin glargineformulation in combination with oral antihyperglycemic drugs(s). Example6 is a substudy of the trial described in example 2. No negative effectswere seen on HbA1c (Table 67) and on fasting plasma glucose (Table 68).The overall incidence of hypoglycemia was similar in both regimensregardless of the category of hypoglycemia (Table 70).

An aspect of the present invention relates to an aqueous pharmaceuticalformulation for use in the treatment of Type I or Type II DiabetesMellitus, wherein the treatment reduces the risk of nocturnalhypoglycemia, said formulation comprising 200-1000 U/mL [equimolar to200-1000 IU human insulin] of insulin glargine, with the proviso thatthe concentration of said formulation is not 684 U/mL of insulinglargine. The present invention relates to an aqueous pharmaceuticalformulation for use in the reduction of the risk of nocturnalhypoglycemia.

The formulation of the present invention can reduce the incidence ofnocturnal hypoglycemia when administered to a Diabetes Mellitus patient,as described herein. “Reduction of the incidence of nocturnalhypoglycemia” includes reduction of the number of nocturnal hypoglycemicevents, and/or the severity of nocturnal hypoglycemia events. Theformulation as described herein is suitable for use in the reduction ofthe incidence of nocturnal hypoglycemia.

The formulation of the present invention can prevent nocturnalhypoglycemia when administered to a Diabetes Mellitus patient, asdescribed herein. “Prevention of nocturnal hypoglycemia” includesreduction of the number of nocturnal hypoglycemic events and/or theseverity of nocturnal hypoglycemia events. The formulation as describedherein is suitable for use in the prevention of nocturnal hypoglycemia.

The formulation of the present invention is suitable for use in thereduction of the number of nocturnal hypoglycemic events and/or theseverity of nocturnal hypoglycemia events.

In the present invention, hypoglycemia is a condition wherein a diabetesmellitus type 2 patient experiences a plasma glucose concentration ofbelow 70 mg/dL (or below 3.9 mmol/L), below 60 mg/dL (or below 3.3mmol/L), below 54 mg/dL (or below 3.0 mmol/L), below 50 mg/dL, below 40mg/dL, or below 36 mg/dL.

In the present invention, “symptomatic hypoglycemia” or “symptomatichypoglycemic event” is a condition associated with a clinical symptomthat results from the hypoglycemia, wherein the plasma glucoseconcentration can be below 70 mg/dL (or below 3.9 mmol/L), below 60mg/dL (or below 3.3 mmol/L), below 54 mg/dL (or below 3.0 mmol/L), below50 mg/dL, or below 40 mg/dL. A clinical symptom can be, for example,sweating, palpitations, hunger, restlessness, anxiety, fatigue,irritability, headache, loss of concentration, somnolence, psychiatricdisorders, visual disorders, transient sensory defects, transient motordefects, confusion, convulsions, and coma. In the method of the presentinvention, one or more clinical symptoms of symptomatic hypoglycemia, asindicated herein, can be selected. Symptomatic hypoglycemia may beassociated with prompt recovery after oral carbohydrate administration.

In the present invention, “severe symptomatic hypoglycemia” or “severesymptomatic hypoglycemic event” is a condition with a clinical symptom,as indicated herein, that results from hypoglycemia, wherein the plasmaglucose concentration can be below 70 mg/dL (or below 3.9 mmol/L), below54 mg/dL (or below 3.0 mmol/L) or below 36 mg/dL (or below 2.0 mmol/L).Severe symptomatic hypoglycemia can be associated with acuteneurological impairment resulting from the hypoglycemic event. In asevere symptomatic hypoglycemia, the patient may require the assistanceof another person to actively administer carbohydrate, glucagon, orother resuscitative actions. These episodes may be associated withsufficient neuroglycopenia to induce seizure, unconsciousness or coma.Plasma glucose measurements may not be available during such an event,but neurological recovery attributable to the restoration of plasmaglucose to normal is considered sufficient evidence that the event wasinduced by a low plasma glucose concentration.

The definition of severe symptomatic hypoglycemia may include allepisodes in which neurological impairment is severe enough to preventself-treatment and which were thus thought to place patients at risk forinjury to themselves or others. The acute neurological impairment may beat least one selected from somnolence, psychiatric disorders, visualdisorders, transient sensory defects, transient motor defects,confusion, convulsions, and coma. “Requires assistance” means that thepatient could not help himself or herself. Assisting a patient out ofkindness, when assistance is not required, should not be considered a“requires assistance” incident.

Severe symptomatic hypoglycemia may be associated with prompt recoveryafter oral carbohydrate, intravenous glucose, or/and glucagonadministration.

In the present invention, “documented symptomatic hypoglycemia” or“documented symptomatic hypoglycemic event” is an event during whichtypical symptoms of hypoglycemia accompanied by a measured plasmaglucose concentration of 70 mg/dL 3.9 mmol/L), or less than or equal to54 mg/dL 3.0 mmol/L). Clinical symptoms that are considered to resultfrom a hypoglycemic episode are, e.g., increased sweating, nervousness,asthenia/weakness, tremor, dizziness, increased appetite, palpitations,headache, sleep disorder, confusion, seizures, unconsciousness, coma.

In the present invention, “asymptomatic hypoglycemia” or “asymptomatichypoglycemic event” is an event not accompanied by typical symptoms ofhypoglycemia but with a measured plasma glucose concentration less thanor equal to 70 mg/dL (3.9 mmol/L), or less than or equal to 54 mg/dL(3.0 mmol/L).

In the present invention, “probable symptomatic hypoglycemia” or“probable symptomatic hypoglycemic event” is an event during whichsymptoms of hypoglycemia are not accompanied by a plasma glucosedetermination, but was presumably caused by a plasma glucoseconcentration less than or equal to 70 mg/dL (or less than or equal to3.9 mmol/L), or less than or equal to 54 mg/dL (or less than or equal to3.0 mmol/L); symptoms treated with oral carbohydrate without a test ofplasma glucose.

In the present invention, “relative hypoglycemia” or “relativehypoglycemic event” is an event during which the person with diabetesreports any of the typical symptoms of hypoglycemia, and interprets thesymptoms as indicative of hypoglycemia, but with a measured plasmaglucose concentration greater than 70 mg/dL (or greater than 3.9mmol/L).

In the present invention, “nocturnal hypoglycemia” or “nocturnalhypoglycemic event” is any hypoglycemia of the hypoglycema categories asdescribed above that occurs night-time. “Nocturnal hypoglycemia” can bedefined by the clock time. In particular, nocturnal hypoglycemia is ahypoglycemia that occurs between 00:00 and 05:59 a.m. hours. The patientcan be awake or can wake up because of the event. The patient can alsosleep during the event.

In the present invention, “daytime hypoglycemia” or “daytimehypoglycemic event” is in particular any hypoglycemia of the hypoglycemacategories as described above that occurs between 06:00 a.m. and 23:59.

In the present invention, the nocturnal hypoglycemia can be asymptomatic hypoglycemia, a severe symptomatic hypoglycemia, adocumented symptomatic hypoglycemia, a probable symptomatichypoglycemia, a relative symptomatic hypoglycemia, or an asymptomatichypoglycemia. Preferred is a symptomatic hypoglycemia, more preferably asevere symptomatic hypoglycemia.

“Reducing the risk of hypoglycemia”, as used herein, can includereducing the incidence of hypoglycemia. The incidence of hypoglycemiaper patient year can be computed per patient as: 365.25×(number ofepisodes of hypoglycemia)/(number of days exposed) and summarized bytype of event and treatment group. “Reducing the risk of hypoglycemia”,as used herein, can further include prevention of hypoglycemia in apatient, when the formulation described herein is administered to aDiabetes Mellitus patient, as described herein. “Reducing the risk ofhypoglycemia”, as used herein, can further include reduction of thenumber of nocturnal hypoglycemic events, and/or the severity ofnocturnal hypoglycemia events.

Example 3 and 6 demonstrate that occasional adaptation of injectionintervals of insulin glargine U300 have no negative effects on HbA1c(Tables 50 and 67) and on fasting plasma glucose (Tables 51 and 69). Theoverall incidence of hypoglycemia was similar in administration byadaptable dosing intervals and in administration by a fixed dosinginterval regardless of the category of hypoglycemia (Tables 53 and 70).

An aspect of the present invention relates to an aqueous pharmaceuticalformulation to be administered in adaptable time intervals. This aspectrelates to an aqueous pharmaceutical formulation for use in thetreatment of Type I or Type II Diabetes Mellitus, wherein theformulation is administered once daily to a patient, and wherein thetime interval from the previous administration is in the range of 24.5 hto 28 h or in the range of 20 h to 23.5 h on at least two days per week,and wherein the average time interval from the previous administrationis about 24 h, said formulation comprising 200-1000 U/mL [equimolar to200-1000 IU human insulin] of insulin glargine, with the proviso thatthe concentration of said formulation is not 684 U/mL of insulinglargine.

As used herein, the time interval from the previous administration isthe time interval between two consecutive administrations, in particularinjections.

It is preferred that the formulation comprises 300 U/ml insulin glargin.

In the treatment regimen, the formulation can be administered in a timerange around a fixed time, for example around a fixed time in theevening or in the morning. The average time interval from the previousadministration can about 24 h (see Table 46). An interval of “about 24h” in particular refers to a range of 24 h+/−10 min, a range of 24h+/−20 min, or range of 24 h+/−30 min. The average time interval can becalculated for example, on weekly basis, on monthly basis, or on thebasis of two or three months, or can be calculated on a longer timebasis.

Table 47 describes the dosing regimen compliance in the test group andcontrol group patients in Example 3. The % of injections by patients indifferent dosing interval categories is described. In the control group(fixed dosing interval of 24 h), about 88% of U300 doses were injectedin an interval of 23 to 25 h from previous injection. About 12% of doseswere injected at an interval of less than 23 h or more than 25 h. Takinginto account one injection per day, the patients dosed the U300formulation at an interval of less than 23 h or more than 25 h at lessthan one day per week. In the test group (adaptable dosing interval),about 63% of U300 doses were injected in an interval of 23 to 25 h fromprevious injection. About 37% of doses were injected at an interval ofless than 23 h or more than 25 h. Taking into account one injection perday, the patients dosed the U300 formulation at an interval of less than23 h or more than 25 h at two or three days per week.

The aqueous formulation can be administered with the time intervalspecified herein on at least two days per week, on at least three daysper week, on at least four days per week or on at least five days perweek. The aqueous formulation can be administered with the time intervalspecified herein on at the maximum five days per week, on at the maximumfour days per week or on at the maximum three days per week. Moreparticular, the aqueous formulation is administered with the timeinterval specified herein on two or three days per week, or on two tothree days per week.

“Occasional adaptation” in particular means that the aqueous formulationis administered on two or three days per week with the time intervalspecified herein.

“Days per week”, as indicated herein, can be calculated for example, onweekly basis, on monthly basis, or on the basis of two or three months,or can be calculated on a longer time basis.

“Adaptable injection intervals” means that the time interval from theprevious injection is variable within a predetermined time range. Thetime interval from the previous administration can be in the range of24.5 h to 28 h or in the range of 20 h to 23.5 h. In particular, thetime interval from the previous administration is in the range of 25 hto 28 h or in the range of 20 h to 23 h.

The time interval from the previous administration can also be in therange of 25 h to 27 h or in the range of 21 h to 23 h.

The time interval from the previous administration can also be in therange of 25 h to 26.5 h or in the range of 21.5 h to 23 h.

In this aspect, the excipients of the formulation can be excipients asdescribed herein. The patient to be treated can be a patient asdescribed herein.

The treatment regimen of adaptable time intervals, as described herein,can be combined with the reduction of the risk of nocturnalhypoglycemia, as described herein.

The formulation for use in the treatment of Diabetes Mellitus Type 1 or2 administered in adaptable time intervals, as described herein, can becombined with the use in the treatment of Diabetes Mellitus Type 1 or 2with reduction of the risk of nocturnal hypoglycemia, as describedherein.

In the present invention, normoglycemia may relate to a blood plasmaconcentration of glucose of from 70 mg/dL to 140 mg/dL (corresponding to3.9 mmol/L to 7.8 mmol/L).

The patient to be treated by the formulation as described herein may bea Type I or Type II Diabetes Mellitus patient. Preferable, the patientis a Type II Diabetes Mellitus patient.

The pharmaceutical formulation of the present invention may beadministered in combination with at least one antihyperglycemic agent.In particular, the at least one antihyperglycemic is metformin or/and apharmaceutically acceptable salt thereof. Metformin is the internationalnonproprietary name of 1,1-dimethylbiguanide (CAS Number 657-24-9). Inthe present invention, the term “metformin” includes anypharmaceutically acceptable salt thereof.

In the present invention, metformin may be administered orally. Theskilled person knows formulations of metformin suitable for treatment ofdiabetes mellitus by oral administration. Metformin may be administeredto a patient in need thereof, in an amount sufficient to induce atherapeutic effect. Metformin may be administered in a dose of at least1.0 g/day or at least 1.5 g/day. For oral administration, metformin maybe formulated in a solid dosage form, such as a tablet or pill.Metformin may be formulated with suitable pharmaceutically acceptablecarriers, adjuvants, or/and auxiliary substances.

The formulation of the present invention and metformin may beadministered by different administration routes. Metformin may beadministered orally, and the formulation of the present invention may beadministered parenterally.

The patient to be treated by the formulation of the present inventionmay be a patient suffering from Diabetes Mellitus type 2, whereindiabetes type 2 is not adequately controlled by treatment with at leastone antihyperglycemic alone. The antihyperglycemic may be metformin,wherein administration does not adequately control Diabetes Mellitustype 2, for example after treatment for at least 2 or at least 3 months,for example with a dose of at least 1.0 g/day or at least 1.5 g/day ofmetformin.

In the present invention, a patient the diabetes type 2 is notadequately controlled if at least one physiological parameter describingblood glucose concentration (e.g. the HbA1c value, the pre-injectionSMPG or/and the fasting plasma glucose concentration) exceedsnormoglycemic values, as described herein. In particular, a patient thediabetes type 2 of which is not adequately controlled may have

(i) a HbA1c value in the range of 7% to 10% or even larger,(ii) a pre-injection SMPG of at least 9 mmol/L, or/and(iv) a fasting plasma glucose of at least 8.0 mmol/L.

The patient to be treated by the formulation as described herein mayhave a HbA1c value in the range of 7% to 10% at the onset of treatment.More particular, the patient to be treated may have a HbA1c value of atleast 8%, or a HbA1c value in the range of 8% to 10% at the onset oftreatment of the present invention.

The patient to be treated by the formulation as described herein may bean adult subject. The patient may have an age of at least 50 years, atleast 57 years, at least 58 years, at least 59 years, at least 60 years,at least 65 years, at least 70 years, or at least 75 years at the onsetof treatment of the present invention.

The patient to be treated by the formulation as described herein may bean obese subject at the onset of treatment of the present invention. Inthe present invention, an obese subject may have a body mass index (BMI)of at least 30 kg/m², at least 31 kg/m², at least 32 kg/m², at least 33kg/m², at least 34 kg/m², at least 35 kg/m², at least 36 kg/m², at least37 kg/m², at least 38 kg/m², at least 39 kg/m² or at least 40 kg/m² atthe onset of treatment. It is preferred that the patient has a BMI of atleast 34 kg/m² or of at least 36 kg/m² at the onset of treatment.

The patient to be treated by the formulation as described herein mayhave an increased risk of hypoglycemia, in particular a diabetes type 2patient having experienced at least one hypoglycemic event.

The patient to be treated by the formulation as described herein mayhave received an insulin directly prior to the treatment as describedherein. In particular, the patient may have received a basal insulin,for example in a dose of at least 32 U/day or at least 42 U/day. In thepresent invention, any pre-treatment with a basal insulin can beconsidered. In particular, the basal insulin can be selected frominsulin Glargine, Detemir, NPH, Lente, Ultralente, Novolin, Humalog andmixtures thereof. The mixture may comprise two different basal insulins.For example, a mixture comprising Detemir and Glargine, or a mixturecomprising NPH and Novolin, may be employed. Preferably, the basalinsulin is insulin Glargin, or a mixture comprising insulin Glargine. Inthe present invention, “basal insulin” includes suitablepharmaceutically acceptable salts thereof.

The patient to be treated by the formulation as described herein mayhave received a mealtime short-acting insulin directly prior to thetreatment as described herein. The mealtime short-acting insulin may bean insulin analogue, for example insulin glulisin, insulin lispro, orinsulin aspart.

The formulation as described herein may be administered once or twicedaily. In particular, the formulation as described herein may beadministered once daily, for example in the evening. The formulation asdescribed herein may be administered once daily in the evening at apredetermined time.

The patient may additionally receive a mealtime short-acting insulin.The mealtime short-acting insulin may be an insulin analogue, forexample insulin glulisin, insulin lispro, or insulin aspart.

The patient to be treated by the formulation of the present inventionmay have a pre-injection self-monitored plasma glucose (SMPG)concentration of at least 9 mmol/L, at least 10 mmol/L, at least 10.5mmol/L, or at least 11 mmol/L at the onset of treatment of the presentinvention. In the present invention, self-monitored plasma glucose canbe a fasting SMPG or a pre-injection SMPG (for example, measured 30minutes prior to injection of the formulation described herein).

The patient to be treated may have a fasting plasma glucoseconcentration of at least 7 mmol/L, at least 7.5 mmol/L, at least 8mmol/L, at least 8.5 mmol/L or at least 9 mmol/L at the onset oftreatment of the present invention.

Although the invention is not limited to a insulin glargine U 300formulation but is effective with other higher concentrated formulationsof insulin glargine as outlined in detail in the specification, theclinical study described herein were performed with a insulin glargine U300 formulation.

1 mL of insulin glargine U 300 formulation contains 10.913 mg21^(A)-Gly-30^(B)a-L-Arg-30^(B)b-L-Arg human insulin [equimolar to 300IU human insulin], 90 μg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, HCland NaOH ad pH 4.0; specific gravity 1.006 g/mL

However, variations with regard to the kind of excipients and theirconcentrations are possible.

The pharmaceutical formulation contains 200-1000 U/mL of insulinglargine [equimolar to 200-1000 IU human insulin], wherein theconcentration of said formulation is not 684 U/mL, preferably 250-500U/mL of insulin glargine [equimolar to 250-500 IU human insulin], morepreferred 270-330 U/mL of insulin glargine [equimolar to 270-330 IUhuman insulin], and even more preferred 300 U/mL of insulin glargine[equimolar to 300 IU human insulin].

Surfactants can be added to pharmaceutical formulation, for example,inter alia, non-ionic surfactants. In particular, pharmaceuticallycustomary surfactants are preferred, such as, for example: partial andfatty acid esters and ethers of polyhydric alcohols such as of glycerol,sorbitol and the like (Span®, Tween®, in particular Tween® 20 and Tween®80, Myrj®, Brij®), Cremophor® or poloxamers. The surfactants are presentin the pharmaceutical composition in a concentration of 5-200 μg/ml,preferably of 5-120 μg/ml and particularly preferably of 20-75 μg/ml.

The formulation can additionally contain preservatives (e.g. phenol,m-cresol, p-cresol, parabens), isotonic agents (e.g. mannitol, sorbitol,lactose, dextrose, trehalose, sodium chloride, glycerol), buffersubstances, salts, acids and alkalis and also further excipients. Thesesubstances can in each case be present individually or alternatively asmixtures.

Glycerol, dextrose, lactose, sorbitol and mannitol can be present in thepharmaceutical preparation in a concentration of 100-250 mM, NaCl in aconcentration of up to 150 mM. Buffer substances, such as, for example,phosphate, acetate, citrate, arginine, glycylglycine or TRIS (i.e.2-amino-2-hydroxymethyl-1,3-propanediol) buffer and corresponding salts,are present in a concentration of 5-250 mM, preferably 10-100 mM.Further excipients can be, inter alia, salts or arginine.

The zinc concentration of the formulation is in the range of theconcentration which is reached by the presence of 0-1000 μg/mL,preferably 20-400 μg/mL zinc, most preferably 90 μg/mL. However, thezinc may be present in form of zinc chloride, but the salt is notlimited to be zinc chloride.

In the pharmaceutical formulation glycerol and/or mannitol can bepresent in a concentration of 100-250 mmol/L, and/or NaCl is preferablypresent in a concentration of up to 150 mmol/L.

In the pharmaceutical formulation a buffer substance can be present in aconcentration of 5-250 mmol/L.

A further subject of the invention is a pharmaceutical insulinformulation for use as described herein which contains further additivessuch as, for example, salts which delay the release of insulin. Mixturesof such delayed-release insulins with formulations described above areincluded therein.

A further subject of the invention is directed to a method for theproduction of such pharmaceutical formulations for use as describedherein. For producing the formulations the ingredients are dissolved inwater and the pH is adjusted by using HCl and/or NaOH. Likewise, afurther subject of the invention is directed to the use of suchformulations for the treatment of diabetes mellitus.

A further subject of the invention is directed to the use or theaddition of surfactants as stabilizer during the process for theproduction of insulin, insulin analogs or insulin derivatives or theirpreparations.

The invention further relates to a formulation as described above whichadditionally comprises also a glucagon-like peptide-1 (GLP1) or ananalogue or derivative thereof, or exendin-3 or -4 or an analogue orderivative thereof, preferably exendin-4.

The invention further relates to a formulation as described above inwhich an analogue of exendin-4 is selected from a group comprising

H-desPro³⁶-exendin-4-Lys₆-NH₂ (Lixisenatide, AVE0010),H-des(Pro^(36,37))-exendin-4-Lys₄-NH₂ andH-des(Pro^(36,37))-exendin-4-Lys₆-NH₂,or a pharmacologically tolerable salt thereof.

The invention further relates to a formulation as described above inwhich an analogue of exendin-4 is selected from a group comprising

desPro³⁶ [Asp²⁸]exendin-4 (1-39),desPro³⁶ [IsoAsp²⁸]exendin-4 (1-39),desPro³⁶ [Met(O)¹⁴, Asp²⁸]exendin-4 (1-39),desPro³⁶ [Met(O)¹⁴, IsoAsp²⁸]exendin-4 (1-39),desPro³⁶ [Trp(O₂)²⁵, Asp²⁸]exendin-2 (1-39),desPro³⁶ [Trp(O₂)²⁵, IsoAsp²⁸]exendin-2 (1-39),desPro³⁶ [Met(O)¹⁴Trp(O₂)²⁵, Asp²⁸]exendin-4 (1-39) anddesPro³⁶ [Met(O)¹⁴Trp(O₂)²⁵, IsoAsp²⁸]exendin-4 (1-39),or a pharmacologically tolerable salt thereof.

The invention further relates to a formulation as described in thepreceding paragraph, in which the peptide -Lys₆-NH₂ is attached to the Ctermini of the analogues of exendin-4.

The invention further relates to a formulation as described above inwhich an analogue of exendin-4 is selected from a group comprising

H-(Lys)₆-des Pro³⁶ [Asp²⁸]exendin-4(1-39)-Lys₆-NH₂des Asp²⁸Pro³⁶, Pro³⁷, Pro₃₈ exendin-4(1-39)-NH₂,H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-NH₂,H-Asn-(Glu)₅ des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-NH₂,des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,H-des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵]exendin-4(1-39)-NH₂,H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-NH₂,H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵,Asp²⁸]exendin-4(1-39)-NH₂,des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵,Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵,Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,des Met(O)¹⁴ Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ exendin-4(1-39)-NH₂,H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-NH₂,H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-NH₂,des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴,Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,H-Asn-(Glu)₅ des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-Lys₆-NH₂,des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵]exendin-4(1-39)-NH₂,H-(Lys)₆-des Pro³⁶′ Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵,Asp²⁸]exendin-4(1-39)-NH₂,H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-NH₂,des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵,Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-(Lys)₆-des Pro³⁶′ Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵,Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆-NH₂,or a pharmacologically tolerable salt thereof.

The invention further relates to a formulation as described above whichadditionally comprises Arg³⁴, Lys²⁶(N^(ε)(γ-glutamyl(N^(α)-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or apharmacologically tolerable salt thereof.

In one embodiment, the present invention is directed to an aqueouspharmaceutical formulation for use as described herein comprisinginsulin glargine in the range of 200-1000 U/mL [equimolar to 200-1000 IUhuman insulin], preferably 200 U/ml to 650 U/mL, still preferably 700U/mL to 1000 U/ml, more preferably 270-330 U/mL and most preferably in aconcentration of 300 U/mL, with the proviso that the concentration ofsaid formulation is not 684 U/mL of insulin glargine.

Additionally, the formulation can also comprise an analogue ofexendin-4, such, for example, lixisentatide, exenatide and liraglutide.These exendin-4 analogues are present in the formulation in the range of0.1 μg to 10 μg per U insulin glargine, preferably 0.2 to 1 μg per Uinsulin glargine, and more preferably 0.25 μg to 0.7 μg per U insulinglargine. Lixisenatide is preferred.

Additionally, the aqueous pharmaceutical formulation can comprise one ormore excipients selected from a group comprising zinc, m-cresol,glycerol, polysorbate 20 and sodium. Specifically, the aqueouspharmaceutical formulation can comprise 90 μg/mL zinc, 2.7 mg/mLm-cresol and 20 mg/ml glycerol 85%. Optionally, the aqueouspharmaceutical formulation can comprise 20 μg/mL polysorbate 20.

The pH of the aqueous pharmaceutical formulation as described herein canbe 4.6 or lower, preferably 4.5 or lower.

The pH of the aqueous pharmaceutical formulation as described herein canalso be in the range from 3.4 to 4.6, preferably in the range from 4 to4.5.

Another aspect of the present invention is directed to a method fortreating a disease or condition as described herein, in particular amethod for treating Type I or Type II Diabetes Mellitus comprisingadministering to said patient the aqueous pharmaceutical composition ofthe present invention to a diabetic patient, wherein treatment reducesthe risk of nocturnal hypoglycemia. The method preferably refers totreatment of Type II Diabetes Mellitus. Preferred among the variousdisclosed concentration ranges is a concentration of 300 U/mL. Furtherthe aqueous pharmaceutical formulation also can comprise zinc, m-cresol,glycerol, polysorbate 20 and sodium and mixtures thereof in the rangesdisclosed herein in relation to the aqueous pharmaceutical formulationof the present invention. In a preferred embodiment the aqueouspharmaceutical formulation also comprises 0.1 μg to 10 μg lixisenatideper U insulin glargine. The nocturnal hypoglycemia can be any nocturnalhypoglycemia, as defined herein. The patient can be any patient asdefined herein.

The insulin is administered preferably once daily but can beadministered twice daily as needed. Dosage requirements are a functionof the needs of the individual patient determined by the achievement ofnormal or acceptable blood glucose levels.

The method can also be a method of treating Type I or Type II DiabetesMellitus in a patient comprising administering to said patient anaqueous pharmaceutical composition as described herein, wherein theformulation is administered once daily, and wherein the time intervalfrom the previous administration is in the range of 24.5 h to 28 h or inthe range of 20 h to 23.5 h on at least two days per week, and whereinthe average time interval from the previous administration is about 24h. The time interval can be a time interval as defined herein. Theaqueous formulation can be administered on at least three days per week,on at least four days per week or on at least five days per week withthe time interval specified herein. The method preferably refers totreatment of Type II Diabetes Mellitus. Preferred among the variousdisclosed concentration ranges is a concentration of 300 U/mL. Furtherthe aqueous pharmaceutical formulation also can comprise zinc, m-cresol,glycerol, polysorbate 20 and sodium and mixtures thereof in the rangesdisclosed herein in relation to the aqueous pharmaceutical formulationof the present invention. In a preferred embodiment the aqueouspharmaceutical formulation also comprises 0.1 μg to 10 μg lixisenatideper U insulin glargine. The patient can be any patient as definedherein.

The treatment method of Diabetes Mellitus Type 1 or 2 administered inadaptable time intervals, as described herein, can be combined with themethod of treatment of Diabetes Mellitus Type 1 or 2 with reduction ofthe risk of nocturnal hypoglycemia, as described herein.

Yet another aspect of the present invention is directed to the use of anaqueous formulation as described herein for the manufacture of amedicament for the treatment of a disease or condition as describedherein, in particular for the treatment of Type I or Type II DiabetesMellitus, wherein the treatment reduces the risk of nocturnalhypoglycemia. The use preferably refers to treatment of Type II DiabetesMellitus. Preferred among the various disclosed concentration ranges isa concentration of 300 U/mL. Further the aqueous pharmaceuticalformulation also can comprise zinc, m-cresol, glycerol, polysorbate 20and sodium and mixtures thereof in the ranges disclosed herein inrelation to the aqueous pharmaceutical formulation of the presentinvention. In a preferred embodiment the aqueous pharmaceuticalformulation also comprises 0.1 μg to 10 μg lixisenatide per U insulinglargine. The nocturnal hypoglycemia can be any nocturnal hypoglycemia,as defined herein. The patient can be any patient as defined herein.

The insulin is administered preferably once daily but can beadministered twice daily as needed. Dosage requirements are a functionof the needs of the individual patient determined by the achievement ofnormal or acceptable blood glucose levels.

Another aspect refers to the use of an aqueous formulation as describedherein for the manufacture of a medicament for treating Type I or TypeII Diabetes Mellitus in a patient comprising administering to saidpatient an aqueous pharmaceutical composition as described herein,wherein the formulation is administered once daily, and wherein the timeinterval from the previous administration is in the range of 24.5 h to28 h or in the range of 20 h to 23.5 h on at least two days per week,and wherein the average time interval from the previous administrationis about 24 h. The time interval can be a time interval as definedherein. The aqueous formulation can be administered on at least threedays per week, on at least four days per week or on at least five daysper week with the time interval specified herein. The method preferablyrefers to treatment of Type II Diabetes Mellitus. Preferred among thevarious disclosed concentration ranges is a concentration of 300 U/mL.Further the aqueous pharmaceutical formulation also can comprise zinc,m-cresol, glycerol, polysorbate 20 and sodium and mixtures thereof inthe ranges disclosed herein in relation to the aqueous pharmaceuticalformulation of the present invention. In a preferred embodiment theaqueous pharmaceutical formulation also comprises 0.1 μg to 10 μglixisenatide per U insulin glargine. The patient can be any patient asdefined herein.

The use for the manufacture of a medicament for the treatment ofDiabetes Mellitus Type 1 or 2 administered in adaptable time intervals,as described herein, can be combined with the use for the manufacture ofa medicament for the treatment of Diabetes Mellitus Type 1 or 2 withreduction of the risk of nocturnal hypoglycemia, as described herein.

The invention relates, inter alia, to the following items:

-   -   1. An aqueous pharmaceutical formulation for use in the        treatment of Type I or Type II Diabetes Mellitus, wherein the        treatment reduces the risk of nocturnal hypoglycemia, said        formulation comprising 200-1000 U/mL [equimolar to 200-1000 IU        human insulin] of insulin glargine, with the proviso that the        concentration of said formulation is not 684 U/mL of insulin        glargine.    -   2. The aqueous formulation for use of item 1 comprising 200 U/ml        to 650 U/mL of insulin glargine.    -   3. The aqueous formulation for use of item 1 comprising 700 U/ml        to 1000 U/mL of insulin glargine.    -   4. The aqueous formulation for use of item 2 comprising 270-330        U/mL of insulin glargine [equimolar to 270-330 IU human        insulin].    -   5. The aqueous formulation for use of item 4 comprising 300 U/mL        of insulin glargine [equimolar to 300 IU human insulin].    -   6. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the nocturnal hypoglycemia is selected        from symptomatic hypoglycemia, severe symptomatic hypoglycemia,        documented symptomatic hypoglycemia, probable symptomatic        hypoglycemia, relative symptomatic hypoglycemia, and        asymptomatic hypoglycemia.    -   7. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the patient to be treated has a HbA1c        value of at least 8% at the onset of treatment.    -   8. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the patient to be treated has an age of        at least 60 years at the onset of treatment.    -   9. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the patient to be treated has a BMI of        at least 30 kg/m² at the onset of treatment.    -   10. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the patient to be treated received a        basal insulin directly prior to the treatment.    -   11. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the patient to be treated received a        mealtime short-acting insulin directly prior to the treatment.    -   12. The aqueous pharmaceutical formulation for use of item 10 or        11, wherein the patient to be treated has a pre-injection SMPG        of at least 9 mmol/L at the onset of treatment.    -   13. The aqueous pharmaceutical formulation for use of item 10 or        11, wherein the patient to be treated has a fasting plasma        glucose concentration of at least 8 mmol/L at the onset of        treatment.    -   14. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the formulation is administered once        daily in the evening at a predetermined time.    -   15. The aqueous pharmaceutical formulation for use of any of the        foregoing items, wherein the patient additionally receives a        mealtime short-acting insulin.    -   16. The aqueous pharmaceutical formulation for use of any of the        foregoing items comprising an analogue of exendin-4.    -   17. The aqueous formulation for use of item 16, wherein the        analogue of exendin-4 is selected from a group comprising        lixisentatide, exenatide and liraglutide.    -   18. The aqueous formulation for use of item 17 comprising 0.1 μg        to 10 μg lixisenatide per U insulin glargine.    -   19. The aqueous formulation for use of item 18 comprising 0.2 to        1 μg lixisenatide per U insulin glargine.    -   20. The aqueous formulation for use of item 19 comprising 0.25        μg to 0.7 μg lixisenatide per U insulin glargine.    -   21. The aqueous formulation for use of any of the foregoing        items comprising one or more excipients selected from a group        comprising zinc, m-cresol, glycerol, polysorbate 20 and sodium.    -   22. The aqueous formulation for use of item 21 comprising 90        μg/mL zinc, 2.7 mg/mL m-cresol and 20 mg/ml glycerol 85%.    -   23. The aqueous formulation for use of item 21 comprising 90        μg/mL zinc, 2.7 mg/mL m-cresol, 20 μg/mL polysorbate 20 and 20        mg/mL glycerol 85%.    -   24. The aqueous formulation for use of any of the foregoing        items, wherein the pH is between 3.4 and 4.6.    -   25. The aqueous formulation for use of item 24, wherein the pH        is 4.    -   26. The aqueous formulation for use of item 24, wherein the pH        is 4.5.    -   27. The pharmaceutical formulation for use of any one of the        items 1 to 26, wherein the Diabetes Mellitus is Type II Diabetes        Mellitus.    -   28. The pharmaceutical formulation for use of item 27, wherein        the Diabetes Mellitus Type II is not adequately controlled with        at least one oral antihyperglycemic alone.    -   29. The pharmaceutical formulation for use of item 28, wherein        the at least one oral antihyperglycemic is metformin.    -   30. The pharmaceutical formulation for use of item 29, wherein a        treatment with at least 1.5 g/day of metformin does not        adequately control the Diabetes Mellitus.    -   31. The aqueous pharmaceutical formulation for use of any of the        items 27 to 30, administered in combination with at least one        oral antihyperglycemic agent.    -   32. The aqueous pharmaceutical formulation for use of item 31,        wherein the at least one antihyperglycemic agent is metformin.    -   33. The aqueous pharmaceutical formulation for use of any one of        the preceding items, wherein the formulation is administered        once daily, and wherein the time interval from the previous        administration is in the range of 24.5 h to 28 h or in the range        of 20 h to 23.5 h on at least two days per week, and wherein the        average time interval from the previous administration is about        24 h.    -   34. A method of treating Type I or Type II Diabetes Mellitus in        a patient comprising administering to said patient an aqueous        pharmaceutical composition comprising insulin glargine in a        concentration of 300 U/mL, wherein the treatment reduces the        risk of nocturnal hypoglycemia.    -   35. The method of item 34 wherein said pharmaceutical        composition further comprises excipients selected from the group        consisting of zinc, m-cresol, glycerol, polysorbate 20 and        sodium.    -   36. The method of item 34 wherein said pharmaceutical        composition further comprises 0.1 μg to 10 μg lixisenatide per U        insulin glargine.    -   37. Use of an aqueous formulation according to any of the        foregoing items for the manufacture of a medicament for the        treatment of Type 1 Diabetes Mellitus and Type 2 Diabetes        Mellitus, wherein the treatment reduces the risk of nocturnal        hypoglycemia.    -   38. An aqueous pharmaceutical formulation for use in the        treatment of Type I or Type II Diabetes Mellitus, wherein the        formulation is administered once daily to a patient, and wherein        the time interval from the previous administration is in the        range of 24.5 h to 28 h or in the range of 20 h to 23.5 h on at        least two days per week, and wherein the average time interval        from the previous administration is about 24 h, said formulation        comprising 200-1000 U/mL [equimolar to 200-1000 IU human        insulin] of insulin glargine, with the proviso that the        concentration of said formulation is not 684 U/mL of insulin        glargine.    -   39. The aqueous formulation of item 38 administered on at least        three days per week with the time interval specified in item 38.    -   40. The aqueous formulation of item 38 administered on at least        four days per week with the time interval specified in item 38.    -   41. The aqueous formulation of any one of the items 38 to 40,        wherein the time interval from the previous administration is in        the range of 25 h to 28 h or in the range of 20 h to 23 h.    -   42. The aqueous formulation of any one of the items 38 to 41,        wherein the time interval from the previous administration is in        the range of 25 h to 27 h or in the range of 21 h to 23 h.    -   43. The aqueous formulation of any one of the items 38 to 42,        wherein the time interval from the previous administration is in        the range of 25 h to 26.5 h or in the range of 21.5 h to 23 h.    -   44. The aqueous formulation for use of any one of the items 38        to 43, comprising insulin glargine in an amount as defined in        any one of the items 2 to 5.    -   45. The aqueous formulation for use of any one of the items 38        to 44, wherein the patient is defined as in any one of the items        7 to 15.    -   46. The aqueous formulation for use of any one of the items 38        to 45, further comprising an analogue of exendin-4, as defined        in any one of the items 16 to 20.    -   47. The aqueous formulation for use of any one of the items 38        to 46, further comprising one or more excipients as defined in        any one of the items 21 to 23.    -   48. The aqueous formulation for use of any one of the items 38        to 47, having a pH as defined in any one of the items 24 to 26.    -   49. The aqueous formulation for use of any one of the items 38        to 48, wherein the treatment reduces the risk of nocturnal        hypoglycaemia.    -   50. The aqueous formulation for use of item 49, wherein the        nocturnal hypoglycemia is selected from symptomatic        hypoglycemia, severe symptomatic hypoglycemia, documented        symptomatic hypoglycemia, probable symptomatic hypoglycemia,        relative symptomatic hypoglycemia, and asymptomatic        hypoglycemia.    -   51. The aqueous formulation for use of any one of the items 38        to 50, wherein the Diabetes Mellitus is Type II Diabetes        Mellitus.    -   52. The aqueous formulation for use of item 51, wherein the        Diabetes Mellitus type II is not adequately controlled with a        least one oral antihyperglycemic agent alone, as defined in any        one of the items 28 to 32.    -   53. A method of treating Type I or Type II Diabetes Mellitus in        a patient comprising administering to said patient an aqueous        pharmaceutical composition comprising insulin glargine in a        concentration of 300 U/mL, wherein the formulation is        administered once daily, and wherein the time interval from the        previous administration is in the range of 24.5 h to 28 h or in        the range of 20 h to 23.5 h on at least two days per week, and        wherein the average time interval from the previous        administration is about 24 h.    -   54. The method of item 53 wherein said pharmaceutical        composition further comprises excipients selected from the group        consisting of zinc, m-cresol, glycerol, polysorbate 20 and        sodium.    -   55. The method of item 53 wherein said pharmaceutical        composition further comprises 0.1 μg to 10 μg lixisenatide per U        insulin glargine.    -   56. Use of an aqueous formulation according to any of the        foregoing items for the manufacture of a medicament for the        treatment of Type 1 Diabetes Mellitus and Type 2 Diabetes        Mellitus, wherein the formulation is administered once daily,        and wherein the time interval from the previous administration        is in the range of 24.5 h to 28 h or in the range of 20 h to        23.5 h on at least two days per week, and wherein the average        time interval from the previous administration is about 24 h.    -   57. An article of manufacture comprising a packaging material,        an aqueous formulation according to any of the foregoing items,        and a label or packaging material indicating that the        formulation is administered once daily, and wherein the time        interval from the previous administration is between 21 h and 27        h, and wherein the average time interval from the previous        administration is about 24 h.    -   58. An article of manufacture comprising a packaging material,        an aqueous formulation according to any of the foregoing items,        and a label or packaging material indicating that the        formulation can be given together with other anti-hyperglyaemic        medicinal products.    -   59. An article of manufacture comprising a packaging material,        an aqueous formulation according to any of the foregoing items,        and a label or packaging material indicating that changing from        a once-daily administration of a basal insulin products to a        once daily administration of the formulation can be done        unit-to-unit based on the previous basal insulin dose; and        changing from twice daily administration of a basal insulin        product to once-daily administration of the formulation, the        recommended initial dose of the formulation is 80% of the total        daily dose of basal insulin that is being discontinued.    -   60. An article of manufacture comprising a packaging material,        an aqueous formulation according to any of the foregoing items,        and a label or packaging material indicating that in case the        formulation is given together with a substance that may enhance        the blood-glucose-lowering effect of the formulation selected        from a group comprising anti-hyperglycaemic medicinal products,        angiotensin converting enzyme (ACE) inhibitors, disopyramide,        fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors,        pentoxifylline, propoxyphene, salicylates and sulfonamide        antibiotics, a dose adjustment of the formulation may be needed.    -   61. An article of manufacture comprising a packaging material,        an aqueous formulation according to any of the foregoing items,        and a label or packaging material indicating that in case the        formulation is given together with a substance that may reduce        the blood-glucose-lowering effect of the formulation selected        from a group comprising corticosteroids, danazol, diazoxide,        diuretics, glucagon, isoniazid, oestrogens and progestogens,        phenothiazine derivatives, somatropin, sympathomimetic medicinal        products (e.g. epinephrine [adrenaline], salbutamol,        terbutaline), thyroid hormones, atypical antipsychotic medicinal        products (e.g. clozapine and olanzapine) and protease inhibitors        a dose adjustment of the formulation may be needed.

The application is described below with the aid of the following figuresand examples, which are in no way intended to act restrictively.

LEGENDS

FIG. 1—Main efficacy analysis—Mean HbA1c (%) by visit during the main6-month on-treatment period—mITT population (Example 1). BAS=Baseline,M6LOCF=last value during main 6-month on-treatment (LOCF). LOCF=Lastobservation carried forward.

FIG. 2—Other secondary efficacy endpoints—Mean average pre-injectionSMPG (mmol/L) by visit during the main 6-month on-treatment period—mITTpopulation (Example 1). BAS=Baseline, M6LOCF=last value during main6-month on-treatment (LOCF). LOCF=Last observation carried forward.

FIG. 3—Other secondary efficacy endpoints—Mean 8-point SMPG profile(mmol/l) at baseline and Month 6 endpoint—mITT population (Example 1).LOCF=Last observation carried forward.

FIG. 4—Other secondary efficacy endpoints—Average daily basal insulinand mealtime insulin dose (U) by visit during the main 6-monthon-treatment period—mITT population (Example 1). BAS=Baseline,M6LOCF=last value during main 6-month on-treatment (LOCF). LOCF=Lastobservation carried forward.

FIG. 5—Main efficacy analysis—Mean HbA1c (%) by visit during the main6-month on-treatment period—mITT population (Example 2). BAS=Baseline,M6LOCF=Month-6 endpoint (LOCF), LOCF=Last observation carried forward.Note: For all patients rescued during the 6-month period, the lastpostbaseline HbA1c measurement before rescue and during the 6-monthon-treatment period will be used as the HbA1c endpoint.

FIG. 6—Other secondary efficacy endpoints—Mean average pre-injectionSMPG (mmol/L) by visit during the main 6-month on-treatment period—mITTpopulation (Example 2). BAS=Baseline, M6LOCF=Month 6 endpoint (LOCF).SMPG=Self Monitoring Plasma Glucose. LOCF=Last observation carriedforward. Note: For all patients rescued during the 6-month period, thelast postbaseline average pre-injection SMPG measurement before rescueand during the 6-month on-treatment period will be used as the averagepre-injection SMPG endpoint.

FIG. 7—Other secondary efficacy endpoints—Mean 8-point SMPG profile(mmol/l) at baseline and Month 6 endpoint—mITT population (Example 2).LOCF=Last observation carried forward. SMPG=Self Monitoring PlasmaGlucose. M6 (LOCF)=Month 6 endpoint LOCF. Note: For all patients rescuedduring the 6-month period, the last postbaseline 8-point profile SMPGmeasurement before rescue and during the 6-month on-treatment periodwill be used as the 8-point profile SMPG endpoint.

FIG. 8—Other secondary efficacy endpoints—Average daily basal insulindose (U) by visit during the main 6-month on-treatment period—mITTpopulation (Example 2). BAS=Baseline, M6LOCF=last value during main6-month on-treatment (LOCF). LOCF=Last observation carried forward.Note: For all patients rescued during the 6-month period, the lastpostbaseline insulin dose measurement before rescue and during the6-month on-treatment period will be used as the insulin dose endpoint.

FIG. 9—Main efficacy analysis—Mean HbA1c (%) by visit during the 3-monthcomparative regimen period—mITT sub-study population. BASM6=Baseline(month 6), M9LOCF=last value during the 3-month comparative regimenperiod (LOCF). LOCF=Last observation carried forward.

FIG. 10—Average daily basal (glargine) and mealtime insulin dose (U) byvisit during the 3-month comparative regimen period—mITT sub-studypopulation. BASM6=Baseline (month 6), M9LOCF=last value during the3-month comparative regimen period (LOCF). LOCF=Last observation carriedforward.

FIG. 11—Plot of average glucose (mg/dL) by hour of day during entiretreatment period—CGM population

FIG. 12—Plot of average glucose (mg/dL) by hour of day during entiremorning injection period—CGM population

FIG. 13—Plot of average glucose (mg/dL) by hour of day during entireevening injection period—CGM population

FIG. 14—Main efficacy analysis—Mean HbA1c (%) by visit during the3-month comparative regimen period—mITT sub-study population.BASM6=Baseline (month 6), M9LOCF=last value during the 3-monthcomparative regimen period (LOCF). LOCF=Last observation carriedforward. Note: For all patients rescued during the 3-month comparativeregimen period, the last postbaseline HbA1c measurement before rescueand during sub-study 3-month on-treatment period will be used as theHbA1c endpoint.

FIG. 15—Average daily basal (glargine) insulin dose (U) by visit duringthe 3-month comparative regimen period—mITT sub-study population.BASM6=Baseline (month 6), M9LOCF=last value during the 3-monthcomparative regimen period (LOCF). LOCF=Last observation carriedforward. Note: For all patients rescued during the 3-month comparativeregimen period, the last postbaseline insulin dose measurement beforerescue and during sub-study 3-month on-treatment period will be used asthe insulin dose endpoint.

EXAMPLE 1: 6-MONTH, MULTICENTER, RANDOMIZED, OPEN-LABEL, PARALLEL-GROUPSTUDY COMPARING THE EFFICACY AND SAFETY OF A NEW FORMULATION OF INSULINGLARGINE AND LANTUS® BOTH PLUS MEALTIME INSULIN IN PATIENTS WITH TYPE 2DIABETES MELLITUS WITH A 6-MONTH SAFETY EXTENSION PERIOD

Synopsis

Phase of Development:

Phase 3

Objectives:

Primary Objective:

To assess the effects on glycemic control of HOE901-U300 in comparisonto Lantus when given as basal insulin in a regimen with mealtime insulinin terms of HbA_(1c) change over a period of 6 months in patients withtype 2 diabetes mellitus.

Main Secondary Objectives:

To compare HOE901-U300 and Lantus in terms of occurrence of nocturnalhypoglycemia, change in preinjection plasma glucose, and change invariability of preinjection plasma glucose.

Further Secondary Objectives:

-   -   To compare HOE901-U300 and Lantus in terms of reaching target        HbA_(1c) values and controlled plasma glucose;    -   To compare HOE901-U300 and Lantus in terms of treatment        satisfaction of patients using the Diabetes Treatment        Satisfaction Questionnaire (status) (DTSQs) (not presented in        KRM);    -   To assess the safety and tolerability of HOE901-U300.

Methodology:

The randomization was 1:1 (HOE901-U300 versus Lantus) and was stratifiedaccording to HbA_(1c) values at screening (<8.0%; ≥8.0%). The samplesize (400 with HOE901-U300 and 400 with Lantus) was chosen to ensuresufficient power for the primary endpoint (change in HbA_(1c) frombaseline to endpoint [Month 6]) as well as to allow conclusions on thefirst main secondary endpoint (occurrence of nocturnal hypoglycemia).

Number of patients: Planned: 800 Randomized: 807 (400 per treatment arm)Treated: 806 Evaluated: efficacy: 804 Safety: 806

Diagnosis and Criteria for Inclusion:

Inclusion criteria: Patients with type 2 diabetes mellitus as defined byWHO; signed written informed consent. Key exclusion criteria: Age<18years; HbA_(1c)<7.0% or >10% at screening; diabetes other than type 2diabetes mellitus; less than 1 year on basal plus mealtime insulin andself-monitoring of blood glucose; total daily dose insulin glargine <42U or equivalent dose of NPH in the last 4 weeks prior to the study (ifNPH was used as basal insulin prior to the study).

Study Treatments

Investigational Medicinal Products:

Tested drug: HOE901-U300; Control drug: Lantus

Formulations:

HOE901-U300 (insulin glargine 300 U/mL solution) is a sterile,non-pyrogenic, clear, colorless solution in a glass cartridge that hasbeen assembled in a pen-injector (prefilled ie, disposable pen). Lantus(insulin glargine 100 U/mL solution) is a sterile, non-pyrogenic, clear,colorless solution supplied in the marketed Solostar® (prefilled ie,disposable pen).

Route of Administration:

subcutaneous injection

Dose Regimen:

Once daily injection in the evening. The injection time was fixed at thetime of randomization and was to be maintained for the duration of thestudy.

HOE901-U300 or Lantus will be injected once daily subcutaneously in theevening, ie, anytime immediately prior to the evening meal untilbedtime. The injection time will be always at the same time within thistime window and will be fixed at randomization at the discretion of thepatient/investigator. Patients will continue with their mealtime insulinanalogue.

Starting Dose:

Patients on Lantus or NPH once daily prior to the baseline visit: thedaily dose (U) of HOE901-U300 or Lantus was equal to the median of thetotal daily basal insulin doses in the last 3 days prior to the baselinevisit.

Patients on NPH More than Once Daily Prior to the Baseline Visit:

the daily dose of for HOE901-U300 or Lantus (U) was to be approximately20% less than the median of the total daily NPH insulin doses in thelast 3 days prior to the baseline visit.

The basal insulin dose was adjusted once weekly to achieve fasting SMPGin the target range of 80 to 100 mg/dL (4.4 to 5.6 mmol/L):

-   -   by +3 U, if the median fasting SMPG of last 3 days was in the        range of >100 mg/dL and <140 mg/dL (>5.6 and <7.8 mmol/L)    -   by +6 U, if the median fasting SMPG of last 3 days was 140 mg/dL        (≥7.8 mmol/L)    -   by −3 U, if the median fasting SMPG of last 3 days was in the        range of ≥60 mg/dL and <80 mg/dL (≥3.3 and <4.4 mmol/L).

Mealtime insulin doses were to be adjusted to optimize glycemic controlafter basal insulin doses have been optimized. Bolus insulin doses couldbe reduced as basal insulin doses were increased.

Noninvestigational Medicinal Products:

Patients in both treatment groups were to continue with their mealtimeinsulin analogue during the study. Patients on concomitant metformintreatment were to continue during the study on a stable dose as receivedprior to the study, unless safety concerns necessitated a dose reductionor discontinuation of metformin.

Duration of Treatment:

Up to 12 months

Duration of Observation:

up to 54 weeks (up to 2-week screening period+6-month efficacy andsafety period+6-month safety extension period+2-day safety follow-up).

The analysis period for efficacy and safety is the main 6-monthon-treatment period. Results presented in the present KRM refer to thisperiod.

Criteria for Evaluation:

Efficacy:

Primary Efficacy Endpoint:

change in HbA_(1c) from baseline to endpoint (Month 6).

Main Secondary Endpoints:

incidence of patients (%) with at least one nocturnal hypoglycemiabetween start of Week 9 and endpoint (month 6), indicated as severeand/or confirmed by plasma glucose ≤70 mg/dL (3.9 mmol/L); change inpreinjection SMPG from baseline to endpoint (Month 6) and change invariability of preinjection SMPG from baseline to endpoint (Month 6).

Safety:

Hypoglycemia, occurrence of adverse events particularlytreatment-emergent adverse events (TEAEs) and serious adverse events(SAEs), injection site reactions and hypersensitivity reactions.Following information not presented in KRM: physical examination, othersafety information including clinical laboratory data, vital signs(including body weight), 12-lead ECG and anti-insulin antibodies.

Statistical Methods:

The primary efficacy endpoint (change in HbA_(1c) from baseline toendpoint [Month 6]) was analyzed using an analysis of covariance(ANCOVA) model with treatment, strata of screening HbA_(1c) (<8.0 and≥8.0%), and country as fixed effects and using the HbA_(1c) baselinevalue as a covariate. Differences between HOE901-U300 and Lantus andtwo-sided 95% confidence intervals were estimated within the frameworkof ANCOVA.

A stepwise closed testing approach was used for the primary efficacyendpoint to assess non-inferiority and superiority sequentially. Step 1assessed non inferiority of HOE901-U300 versus Lantus. To assessnon-inferiority, the upper bound of the two sided 95% CI for thedifference in the mean change in HbA1c from baseline to endpoint betweenHOE901-U300 and Lantus was compared with a predefined non inferioritymargin of 0.4% for HbA1c. Non-inferiority would be demonstrated if theupper bound of the two-sided 95% CI of the difference betweenHOE901-U300 and Lantus on mITT population is <0.4%. Step 2 assessedsuperiority of HOE901-U300 versus Lantus only if non inferiority wasdemonstrated. The superiority of HOE901-U300 over Lantus wasdemonstrated if the upper bound of the two-sided 95% CI of thedifference between HOE901-U300 and Lantus on mITT population was <0.

Only if non-inferiority of HOE901-U300 versus Lantus had beendemonstrated for the primary endpoint, would testing for superiority ofHOE901-U300 over Lantus on the main secondary endpoints occur within theframe of a hierarchical testing procedure. Safety analyses weredescriptive, based on the safety population.

Summary:

Population Characteristics:

A total of 807 patients with type 2 diabetes were randomized toHOE901-U300 (n=404) or to Lantus (n=403); 806 patients were exposed toIMP (safety population). The mITT population (efficacy population)included 804 patients.

Overall, a comparable number of patients in each treatment groupdiscontinued the study prematurely (HOE901-U300: 30/404, 7.4%; Lantus31/403, 7.7%).

Demographics and baseline characteristics were well-balanced between thetreatment groups. The mean age of the study population was 60 years,246/807 (30.4%) were 65 years. The mean BMI at baseline was 36.6 kg/m².The mean duration of diabetes prior to study start was 15.8 years, themean duration of prior treatment with basal insulin was 6.6 years andthe median total daily insulin dose was 1.1 U/kg body weight. In bothtreatment groups, mean HbA1c at baseline was 8.14%.

Efficacy Results:

Primary endpoint: The LS mean change in HbA1c from baseline to endpoint(Month 6) was similar in both treatment groups (HOE901-U300: −0.83% (95%CI [−0.946; −0.709]); Lantus: −0.83% (95% CI [−0.944; −0.706]).Non-inferiority of HOE901-U300 versus Lantus was demonstrated with theLS mean difference in HbA1c versus Lantus of −0.00% (95% CI [−0.112;0.107]) with the upper bound lower than the predefined non-inferioritymargin of 0.4%. Superiority of HOE901-U300 versus Lantus was notdemonstrated.

1^(st) Main Secondary Endpoint:

The incidence of patients with at least one nocturnal severe and/orconfirmed hypoglycemia between start of Week 9 and Month 6 was lower inthe HOE901-U300 group [136/404 (33.7%)] than in the Lantus group[180/400 (45.0%)]. Superiority of HOE901-U300 versus Lantus was shownwith a relative risk of 0.75 (95% CI [0.63, 0.89]) (p=0.0010).

2^(nd) Main Secondary Endpoint:

The LS mean change in pre-injection SMPG from baseline to endpoint(Month 6) was similar in the HOE901-U300 (−0.90 mmol/L) and Lantusgroups (−0.84 mmol/L). The difference between the treatment groups wasnot statistically significant (LS mean difference −0.06 (95% CI [−0.383,0.255], p=0.6921).

3^(rd) Main Secondary Endpoint:

As the superiority of HOE901-U300 versus Lantus was not demonstrated forthe second main secondary endpoint, no further test was performed forthe third main secondary endpoint (decrease in variability ofpre-injection SMPG at Month 6, which was similar for both treatmentgroups).

Other Secondary Efficacy Endpoints (Month 6):

Both the proportion of patients having reached HbA1c<7% and the meanchange in FPG were similar between treatment groups. Graphicalpresentation of the 8-point SMPG profiles of HOE901-U300- andLantus-treated patients showed a marked decrease in plasma glucose atendpoint (Month 6) compared with baseline. The profiles of the 2treatment groups are almost superimposable at both baseline andendpoint.

The increase of basal insulin dose in the HOE901-U300 group resulted ina mean daily dose of 103 U at Month 6 compared to Lantus group with amean daily dose of 94 U (the mean basal insulin dose at baseline was 70U in both treatment groups). The increase of the daily mealtime insulindose was comparable between treatment groups with a small increase inthe first two weeks. Thereafter, mealtime insulin doses remained stable.

Safety Results:

Overall, hypoglycemia was reported by a consistently lower percentage ofpatients in the HOE901-U300 group than in the Lantus group. Thisdifference was even more pronounced during the first 2 months of studytreatment as well as for events of nocturnal hypoglycemia. During themain 6-month on-treatment period severe hypoglycemia was reported in21/404 (5.2%) of HOE901-U300 treated patients and 23/402 (5.7%) ofLantus treated patients.

The percentages of patients with any TEAEs (HOE901-U300, 222/404[55.0%]; Lantus: 215/402 [53.5%]) or with serious TEAEs (HOE901-U300, 25[6.2%]; Lantus, 21 [5.2%]) were similar between both groups. A similarproportion of patients experienced serious cardiac TEAEs (SOC—cardiacdisorders) in both treatment groups (HOE901-U300: n=5, 1.2%; Lantus:n=7; 1.7%).

Six patients died during the study, 3 (0.7%) in each treatment group. Ofthese, 4 patients died during the first 6 months, 2 (0.5%) in eachtreatment group. The events with fatal outcome in the three patients inthe HOE901-U300 group included the following conditions: infectedthrombosis and embolism in the heart, bronchogenic carcinoma withmetastasis and—for the third patient—pulmonary emboli. The leading causeof the fatal events in the three patients in the Lantus group included:chronic depression and intoxication with medication, one patient hadmultitude of conditions including worsening of chronic heart failure(NYHA IV), chronic kidney failure stage 4 with acute decompensation,decompensated diabetes and diabetic nephropathy contributing to thefatal outcome and the last patient suffered acute cardiopulmonary arrestof unknown etiology. None of the deaths were considered related to studydrug. A similar number of patients in both treatment groups experiencedTEAEs leading to permanent treatment discontinuation (HOE901-U300: n=6,1.5%; Lantus: n=7, 1.7%).

Hypersensitivity reactions during the main 6-month on-treatment periodwere reported at a similar rate in both treatment groups (HOE901-U300:n=3, 0.7%; Lantus: n=2, 0.5%).

Overall injection site reactions during the main 6-month on-treatmentperiod showed similar rate in both treatment groups (HOE901-U300: n=9,2.2%; Lantus: n=6, 1.5%).

Conclusions:

In this study in 807 patients with T2DM on basal insulin in combinationwith mealtime insulin, the baseline characteristics and demographiccharacteristics were well balanced across treatment groups.Non-inferiority of HOE901-U300 versus Lantus was shown for the primaryefficacy endpoint (change in HbA1c from baseline to endpoint [Month 6]).The incidence of patients (%) reporting nocturnal hypoglycemia (severeand/or confirmed by SMPG ≤70 mg/dL [3.9 mmol/L]) between start of Week 9and Month 6 was significantly lower in the HOE901-U300 group than in theLantus group (33.7% and 45% respectively, RR of 0.75, p-value 0.0010;1^(st) main secondary efficacy endpoint). Comparable results between thetreatment groups were found for other secondary endpoints such aspre-injection plasma glucose, variability of pre-injection plasmaglucose, number of patients reaching target HbA1c, mean change of FPGand 8-point profiles of plasma glucose.

Overall incidence of hypoglycemia (% of patients with at least oneevent) during the main 6-month on-treatment period was lower in theHOE901-U300 group than in the Lantus group regardless of the category ofhypoglycemia.

HOE901-U300 was well tolerated during the main 6-month on-treatmentperiod of the study and no specific safety concerns were observed.

Summary of the efficacy and safety results of the twelve month EDITION 1extension study

-   -   HbA1c: during the safety extension period (from the main study        endpoint [Month 6] to the End of Treatment [Month 12]) HbA1c        remained stable and was comparable in both treatment groups    -   hypoglycemia: overall, similarly as during the main 6-month        treatment period, during the whole study on-treatment period        hypoglycemia occurred in a similar or lower percentage of        patients in the HOE901-U300 group than in the Lantus group    -   safety: HOE901-U300 was well tolerated during the study and no        specific safety concerns were observed; during the whole        treatment period, the percentages of patients with any TEAEs        were similar in both groups (289/404 [71.5%] in the HOE901-U300        and 278/402 [69.2%] in the Lantus treatment group), with no        specific SOC contributing. Serious TEAEs were reported by a        similar number of patients: (53 [13.1%]) in the HOE901-U300 and        62 [15.4%] in the Lantus treatment group). Two (0.5%) patients        in the HOE901-U300 and 4 (1.0%) patient in the Lantus treatment        group had TEAE leading to death during the whole study        on-treatment period    -   body weight: in both treatment groups, during the whole study        on-treatment period there was small increase in body weight        (1.17 kg for HOE901-U300 and 1.40 kg for Lantus).

1 RESULTS

1.1 STUDY PATIENTS

1.1.1 Study Disposition

TABLE 1 Patient disposition—Randomized population HOE901-U300 Lantus (N= 404) (N = 403) Randomized and treated 404 (100%) 402 (99.8%) Completedmain 6-month treatment period 374 (92.6%) 371 (92.1%) Permanentlydiscontinued the treatment  30 (7.4%)  31 (7.7%) during the main 6-monthperiod Subject's request for treatment dis-  21 (5.2%)  20 (5.0%)continuation Randomized and treated 404 (100%) 402 (99.8%) Reason fortreatment discontinuation during the main 6-month period Adverse event 9 (2.2%)  8 (2.0%) Lack of efficacy  1 (0.2%)  1 (0.2%) Poor complianceto protocol  2 (0.5%)  5 (1.2%) Other reasons  18 (4.5%)  17 (4.2%)Status at last study contact of patients who permanently discontinuedthe treatment during the main 6-month period Alive  27 (6.7%)  28 (6.9%)Dead  3 (0.7%)  2 (0.5%) Note: percentages are calculated using thenumber of patients randomized as denominator

TABLE 2 Analysis populations HOE901-U300 Lantus All Randomizedpopulation 404 (100%) 403 (100%) 807 (100%) Efficacy populationsModified Intent-to-Treat 404 (100%) 400 (99.3%) 804 (99.6%) (mITT) Month6 completers 374 (92.6%) 371 (92.1%) 745 (92.3%) Safety population 404402 806 Note: For the safety population, patients are tabulatedaccording to treatment actually received (as treated) For the otherpopulations, patients are tabulated according to their randomizedtreatment

1.1.2 Demographics and Baseline Characteristics

TABLE 3 Demographics and patient characteristics at baseline—Randomizedpopulation HOE901-U300 Lantus All (N = 404) (N = 403) (N = 807) Age(years) Number 404 403 807 Mean (SD)  60.1 (8.5)  59.8 (8.7)  60.0 (8.6)Median  61.0  60.0  61.0 Min:Max  28:83  32:86  28:86 Age Group (years)[n (%)] Number 404 403 807 <65 277 (68.6%) 284 (70.5%) 561 (69.5%)[65-75[ 114 (28.2%) 105 (26.1%) 219 (27.1%) ≥75  13 (3.2%)  14 (3.5%) 27 (3.3%) Gender [n (%)] Number 404 403 807 Male 217 (53.7%) 210(52.1%) 427 (52.9%) Female 187 (46.3%) 193 (47.9%) 380 (47.1%) Race [n(%)] Number 404 403 807 Caucasian/White 371 (91.8%) 374 (92.8%) 745(92.3%) Black  26 (6.4%)  21 (5.2%)  47 (5.8%) Asian/Oriental  6 (1.5%) 5 (1.2%)  11 (1.4%) Other  1 (0.2%)  3 (0.7%) 4  (0.5%) Ethnicity [n(%)] Number 404 403 807 Hispanic  26 (6.4%)  25 (6.2%)  51 (6.3%) NotHispanic 378 (93.6%) 378 (93.8%) 756 (93.7%) World region [n (%)] Number404 403 807 Northern America 206 (51.0%) 207 (51.4%) 413 (51.2%) WesternEurope  33 (8.2%)  33 (8.2%)  66 (8.2%) Eastern Europe 147 (36.4%) 141(35.0%) 288 (35.7%) Rest of the world  18 (4.5%)  22 (5.5%)  40 (5.0%)Baseline weight (kg) Number 404 403 807 Mean (SD) 106.2 (21.5) 106.4(20.0) 106.3 (20.8) Median 104.3 104.1 104.1 Min:Max  60:197  62:164 60:197 Baseline BMI (kg/m²) Number 404 403 807 Mean (SD)  36.6 (6.8) 36.6 (6.1)  36.6 (6.4) Median  35.8  36.0  35.9 Min:Max  23:62  24:62 23:62 Baseline BMI categories (kg/m²) [n (%)] Number 404 403 807 <25  5(1.2%)  2 (0.5%)  7 (0.9%) [25-30[  54 (13.4%)  47 (11.7%) 101 (12.5%)[30-40[ 241 (59.7%) 244 (60.5%) 485 (60.1%) ≥40 104 (25.7%) 110 (27.3%)214 (26.5%) Baseline estimated GFR (mL/min/1.73 m²) Number 404 403 807Mean (SD)  73.67 (19.32)  74.77 (21.38)  74.22 (20.37) Median  73.62 75.63  74.41 Min:Max  19.9:144.2  15.0:141.5  15.0:144.2 Baselineestimated GFR categories (mL/min/1.73 m²) [n (%)] Number 404 403 807 ≥90 75 (18.6%)  89 (22.1%) 164 (20.3%) [60-90[ 235 (58.2%) 221 (54.8%) 456(56.5%) [30-60[  92 (22.8%)  83 (20.6%) 175 (21.7%) <30  2 (0.5%)  10(2.5%)  12 (1.5%) Randomization strata of screening HbA1c (%) [n (%)]Number 404 403 807 <8 144 (35.6%) 144 (35.7%) 288 (35.7%) ≥8 260 (64.4%)259 (64.3%) 519 (64.3%) BMI = Body Mass Index GFR = Glomerularfiltration rate GFR is derived from MDRD formula

TABLE 4 Summary of disease characteristics at baseline—Randomizedpopulation HOE901-U300 Lantus All (N = 404) (N = 403) (N = 807) Durationof T2D (years) Number 404 403 807 Mean (SD)  15.6 (7.2)  16.1 (7.8) 15.8 (7.5) Median  15.2  15.2  15.2 Min:Max  2:43  2:44  2:44 Categoryof duration of T2D (years) Number 404 403 807 <10  90 (22.3%)  84(20.8%) 174 (21.6%) ≥10 314 (77.7%) 319 (79.2%) 633 (78.4%) Age at onsetof T2D (years) Number 404 403 807 Mean (SD)  45.0 (8.8)  44.2 (9.5) 44.6 (9.2) Median  44.9  44.4  44.7 Min:Max  18:78  15:73  15:78Duration of basal insulin treatment (years) Number 404 403 807 Mean (SD) 6.71 (4.74)  6.48 (4.78)  6.59 (4.76) Median  5.50  5.20  5.40 Min:Max 0.3:32.8  1.0:33.2  0.3:33.2 Previous basal insulin type [n (%)] Number402 399 801 Insulin glargine 372 (92.5%) 365 (91.5%) 737 (92.0%) NPH  30(7.5%)  34 (8.5%)  64 (8.0%) Previous basal insulin daily injectionnumber^(a) [n (%)] Number 403 399 802 Once daily 333 (82.6%) 334 (83.7%)667 (83.2%) Twice daily  70 (17.4%)  65 (16.3%) 135 (16.8%) More thantwice daily  0  0  0 Previous basal insulin daily dose^(b) (U) Number371 363 734 Mean (SD)  69.93 (30.42)  70.17 (28.31)  70.05 (29.38)Median  60.00  60.00  60.00 Q1:Q3  49.00:81.00  50.00:80.00  50.00:80.00Min:Max  42.0:200.0  42.0:200.0  42.0:200.0 Previous basal insulin dailydose^(b) (U/kg) Number 371 363 734 Mean (SD)  0.668 (0.264)  0.667(0.240)  0.667 (0.252) Median  0.598  0.609  0.601 Duration of T2D(years) Q1:Q3  0.487:0.769  0.493:0.770  0.490:0.769 Min:Max  0.30:2.12 0.31:1.76  0.30:2.12 Previous mealtime insulin daily dose^(b) (U)Number 396 397 793 Mean (SD)  57.11 (36.45)  58.42 (37.89)  57.77(37.16) Median  49.30  52.00  50.00 Q1:Q3  32.00:72.80  31.70:75.00 32.00:73.70 Min:Max  5.0:350.0  3.6:280.0  3.6:350.0 Previous mealtimeinsulin daily dose^(b) (U/kg) Number 396 397 793 Mean (SD)  0.537(0.336)  0.540 (0.315)  0.538 (0.325) Median  0.474  0.488  0.480 Q1:Q3 0.332:0.670  0.329:0.687  0.330:0.685 Min:Max  0.06:3.08  0.03:2.30 0.03:3.08 Previous total insulin daily dose^(b) (U) Number 366 361 727Mean (SD) 126.00 (56.57) 127.78 (55.97) 126.88 (56.24) Median 112.00114.00 113.00 Q1:Q3  88.00:149.10  87.00:154.90  87.90:152.00 Min:Max 47.0:530.0  52.4:384.0  47.0:530.0 Previous total insulin dailydose^(b) (U/kg) Number 366 361 727 Mean (SD)  1.193 (0.484)  1.199(0.447)  1.196 (0.465) Median  1.085  1.101  1.096 Q1:Q3  0.875:1.401 0.871:1.388  0.871:1.398 Min:Max  0.50:4.66  0.51:3.13  0.50:4.66 Prioruse of Lantus^(c) Number 404 403 807 Yes 373 (92.3%) 369 (91.6%) 742(91.9%) No  31 (7.7%)  34 (8.4%)  65 (8.1%) Prior use of Metformin^(c)Number 404 403 807 Yes 227 (56.2%) 234 (58.1%) 461 (57.1%) No 177(43.8%) 169 (41.9%) 346 (42.9%) T2D = Type 2 diabetes ^(a)Maximalinjection number of the patient. ^(b)Mean of the patient from thebasal/mealtime/total daily doses during the last 7 days prior torandomization ^(c)Taken within 3 months before screening

1.2 Efficacy Evaluation

1.2.1 Primary Efficacy Endpoint

TABLE 5 Main efficacy analysis—Mean change in HbA1c (%) from baseline toMonth 6 endpoint using LOCF procedure—mITT population (FIG. 1)HOE901-U300 Lantus HbA1c (%) (N = 404) (N = 400) Baseline Number 391 394Mean (SD)  8.14 (0.78)  8.14 (0.76) Median  8.10  8.10 Min:Max  6.5:10.6 6.4:10.3 Month 6 endpoint (LOCF) Number 391 394 Mean (SD)  7.25 (0.85) 7.28 (0.92) Median  7.10  7.20 Min:Max  5.3:10.6  5.2:13.8 Change frombaseline to Month 6 endpoint (LOCF) Number 391 394 Mean (SD)   −0.88(0.81)   −0.86 (0.92) Median   −0.90   −0.90 Min:Max   −3.4:1.8  −3.1:4.6 LS Mean (SE)^(a)   −0.83 (0.060)   −0.83 (0.061) 95% Cl (−0.946 to −0.709)  (−0.944 to −0.706) LS Mean difference   −0.00(0.056) (SE) vs. Lantus^(a) 95% Cl  (−0.112 to 0.107) LOCF = Lastobservation carried forward. ^(a)Analysis of covariance (ANCOVA) modelwith treatment groups (HOE901-U300 and LANTUS), randomization strata ofscreening HbA1c (<8.0, ≥8.0%), and country as fixed effects and baselineHbA1c value as a covariate.

1.2.2 Main Secondary Endpoints

1.2.2.1 Nocturnal Hypoglycemia

TABLE 6 First main secondary efficacy endpoint—Number (%) of patientswith at least one nocturnal hypoglycemia [00:00 to 05:59] occurringbetween start of Week 9 and Month 6 endpoint (using LOCF procedure),indicated as severe and/or confirmed by plasma glucose ≤3.9 mmol/L (70mg/dL)—mITT population HOE901-U300 Lantus (N = 404) (N = 400) Severeand/or confirmed nocturnal hypoglycemia [00:00 to 05:59] n (%) 136(33.7%) 180 (45.0%) RR (95% Cl) vs. Lantus^(a)  0.75 (0.63 to 0.89) —p-value (CMH)  0.0010 — n (%) = number and percentage of patients withat least one nocturnal hypoglycemia event, indicated as severe and/orconfirmed by plasma glucose 3.9 mmol/L (70 mg/dL) ^(a)Based on RRstratified by randomization strata of screening HbA1c (<8.0 or ≥8.0%),using a CMH methodology

1.2.2.2 Pre-Injection Plasma Glucose—Month 6 Endpoint

TABLE 7 Second main secondary efficacy endpoint—Mean change in averagepre- injection SMPG (mmol/L) from baseline to Month 6 endpoint usingLOCF procedure—mITT population (FIG. 2) Average pre-injection SMPGHOE901-U300 Lantus (mmol/L) (N = 404) (N = 400) Baseline Number 365 360Mean (SD)  10.31 (2.58)  10.44 (2.65) Median  10.02  9.98 Min:Max 4.4:20.6  5.6:20.8 Month 6 endpoint (LOCF) Number 365 360 Mean (SD) 9.11 (2.42)  9.28 (2.45) Median  8.77  8.69 Min:Max  3.8:20.3  4.8:19.1Change from baseline to Month 6 endpoint (LOCF) Number 365 360 Mean (SD)  −1.20 (2.84)   −1.16 (2.70) Median   −1.19   −1.24 Min:Max −13.2:8.9−11.3:7.5 LS Mean (SE)^(b)   −0.90 (0.183)   −0.84 (0.183) 95% Cl (−1.260 to −0.543)  (−1.196 to −0.478) LS Mean difference   −0.06(0.162) (SE) vs. Lantus^(b) 95% Cl  (−0.383 to 0.255) p-value(ANCOVA) 0.6921 LOCF = Last observation carried forward. SMPG = Self MonioringPlasma Glucose ^(a)Average is assessed by the mean of at least 3 SMPGcalculated over the 7 days preceding the given visit. ^(b)Analysis ofcovariance (ANCOVA) model with treatment groups (HOE901-U300 andLANTUS), randomization strata of screening HbA1c (<8.0, ≥8.0%), andcountry as fixed effects and baseline average pre-injection SMPG valueas a covariate.

At V1 (week-2), the investigator or a member of the investigationalstaff will provide patients with a blood glucometer and thecorresponding supplies (needles, control solutions, test strips etc.)and with diaries in order to perform self-measurement of plasma glucoseand its recording. Patients will be shown how to accurately measureplasma glucose values with the blood glucometer. The investigator or amember of the investigational staff will explain the need to measureglucose at the times requested for profiles and to correctly record thevalues in the patient diaries. Training is repeated as often asnecessary at the study visits and the investigational staff reviews thepatient's diary at each visit. Blood glucose values will be measured bythe patient using the sponsor-provided blood glucose meter. Patientswill document their SMPG data in the diary.

The patients will be instructed to bring the blood glucometers providedby the sponsor with them to each office visit. The blood glucometersshould be calibrated according to instructions given in the packageleaflet and the investigational site should also check regularly theglucometers using the provided control solutions for data validity.

Starting with V1 (screening visit), the diary includes sections forrecording by patients of

-   -   Study treatment and mealtime insulin: time and dose of        HOE901-U300 or Lantus injections (Lantus or NPH injections        during screening period) and mealtime/bolus insulin analogue        injections;    -   SMPG: time and value of SMPG;        -   1. Fasting SMPG in the morning (prebreakfast)        -   2. SMPG within 30 minutes prior to injection of basal            insulin during 7 days before each visit        -   3. 4-point profile and 8-point profile SMPG        -   4. SMPG related to hypoglycemic events        -   5. Any other SMPG (whatever the reason of measurement)

SMPG measurements are scheduled as follows:

-   -   Fasting plasma glucose (SMPG): The fasting (prebreakfast) SMPG        will be measured daily throughout the study. During the week        before visit 3 (Day 1, Baseline) compliance to the fasting SMPG        measurement schedule will be used to assess eligibility for        entry in the randomized treatment period. During the study, when        uptitration has been completed and fasting (prebreakfast) SMPG        is stable in the target range, at least of 3 measurements per        week should be performed.    -   Plasma glucose within 30 minutes prior to injection of study        drug (preinjection SMPG): Preinjection SMPG will be done within        30 min prior to the injection of the IMP (HOE901-U300 or Lantus)        on at least 7 days before baseline and before each on site visit        throughout the study. At days when 4-point or 8-point profiles        are done: if time of preinjection SMPG is the same as a time        point of the 4-point or 8-point profile, the SMPG value has to        be assigned by the patient in the diary to both (eg,        preinjection PG; bedtime).    -   4-point SMPG profiles (prebreakfast, prelunch, predinner,        bedtime): During the week before baseline visit and during the        first 12 weeks of treatment with IMP, patients will perform        4-point SMPG profiles at least on 3 days per week. Once the        titration goal is reached, the number of 4-point SMPG profiles        can be reduced according to the investigator's judgment but        4-point SMPG profiles at least on 3 days in the week before each        visit are mandatory. It is, however, recommended to perform        4-point SMPG profiles daily throughout the study for optimal        adjustment of the insulin regimen;    -   8-point blood glucose profiles (starting with a measurement at        03:00 am at night; before and 2 hours after breakfast; before        and 2 hours after lunch; before and 2 hours after dinner; at        bedtime): Patients will perform 8-point SMPG profiles at least        one day in the 5 days before each on-site visit. It is, however,        recommended to perform 8-point SMPG profiles at least once        weekly up to week 8, and once every second week thereafter.        Special attention should be paid that the 3.00 a.m. SMPG value        is recorded.    -   SMPG during episodes of symptomatic hypoglycemia: Whenever the        patients feel hypoglycemic symptoms, plasma glucose should be        measured by the patient (or others, if applicable), if possible.        Patients should be instructed to measure plasma glucose levels        prior to the administration of glucose or carbohydrate intake        whenever symptomatic hypoglycemia is suspected, unless safety        considerations necessitate immediate glucose/carbohydrate rescue        prior to confirmation.

The following SMPG values have to be copied into the eCRF:

During the week prior to baseline visit and during the first 12 weeksuntil Visit 8 (week 12):

-   -   Fasting (prebreakfast) SMPG: daily    -   Preinjection SMPG (within 30 minutes prior to injection of the        basal insulin): at 7 days prior to each on-site visit    -   4-point profile SMPG: at 3 different days in each week until        visit 8 (week 12)    -   8-point profile SMPG: 1 profile within 5 days before each        on-site visit    -   SMPG related to hypoglycemic event: whenever documented

Note: following phone call visits the following data at the minimum willbe entered into the e-CRF: fasting (prebreakfast) SMPG over last 3 days,SMPG related to hypoglycemic event: whenever documented. The remainingSMPG data of the week prior to the phone call visits will be enteredinto the e-CRF at a subsequent on-site visit. After Visit 8 (week 12):

-   -   Fasting (prebreakfast) SMPG: during 7 days before each on-site        visit    -   Preinjection SMPG (within 30 minutes prior to injection of the        basal insulin): at 7 days prior to each on-site visit    -   4-point profile SMPG: at 3 different days within 7 days before        each on-site visit    -   8-point profile SMPG: at one day within 5 days before each        on-site visit    -   SMPG related to hypoglycemic event: whenever documented

All glucose values will be used by the investigator to monitor glycemia.

1.2.2.3 Variability of Preinjection SMPG—Month 6 Endpoint

TABLE 8 Third main secondary efficacy endpoint—Mean change invariability of pre-injection SMPG from baseline to Month 6 endpointusing LOCF procedure—mITT population HOE901-U300 Lantus Variability ofpre-injection SMPG (N = 404) (N = 400) Baseline Number 365 360 Mean (SD) 25.55 (12.41)  24.97 (11.82) Median  23.92  24.34 Min:Max  0.0:82.8 1.7:74.3 Month 6 endpoint (LOCF) Number 365 360 Mean (SD)  22.23(11.76)  21.57 (11.47) Median  21.79  20.42 Min:Max  0.0:60.3  0.9:64.1Change from baseline to Month 6 endpoint (LOCF) Number 365 360 Mean (SD)  −3.32 (14.59)   −3.40 (14.54) Median   −2.88   −3.17 Min:Max−62.5:48.1 −54.7:41.7 LS Mean (SE)^(a)   −1.09 (1.222)   −1.11 (1.222)95% Cl  (−3.486 to 1.310)  (−3.508 to 1.292) LS Mean difference (SE) vs.Lantus^(a)  0.02 (1.087) 95% Cl  (−2.114 to 2.154) LOCF = Lastobservation carried forward. SMPG = Self Monioring Plasma GlucoseVariability is assessed by the mean of coefficient of variationcalculated over at least 3 SMPG measured during the 7 days preceding thegiven visit ^(a)Analysis of variance (ANOVA) model with treatment groups(HOE901-U300 and LANTUS), randomization strata of screening HbA1c (<8.0,≥8.0%), and country as fixed effects

1.2.3 Other Secondary Efficacy Endpoints

1.2.3.1 Percentage of Patients with HbA1c <7% at Month 6

TABLE 9 Other secondary efficacy endpoint—Number (%) of patients withHbA1c <7% at Month 6 endpoint (using LOCF procedure) and Number (%) ofpatients with HbA1c <7% at Month 6 endpoint (using LOCF procedure)having experienced no hypoglycemia indicated as severe and/or confirmedby plasma glucose <3 mmol/L (54 mg/dL) during the last 3 months of themain 6-month treatment period—mITT population HOE901-U300 Lantus (N =404) (N = 400) HbA1c <7% Number 391 394 n (%) 155 (39.6%) 161 (40.9%) RR(95% Cl) vs. Lantusa  0.97 (0.83 to 1.14) — HbA1c <7% and no severeand/or confirmed (<3.0 mmol/L;<54 mg/dL) hypoglycemia Number 393 394 n(%)  99 (25.2%)  95 (24.1%) RR (95% Cl) vs. Lantus^(a)  1.05 (0.82 to1.33) — ^(a)Based on RR stratified by randomization strata of screeningHbA1c (<8.0 or ≥8.0%), using a CMH methodology LOCF = Last observationcarried forward. RR = relative risk

1.2.3.2 Change in FPG from Baseline to Month 6 Endpoint

TABLE 10 Other secondary efficacy endpoint - Mean change in FPG (mmol/L)from baseline to Month 6 endpoint using LOCF procedure - mITT populationHOE901-U300 Lantus FPG(mmol/L) (N = 404) (N = 400) Baseline Number 378385 Mean (SD)  8.72 (2.83)  8.90 (2.94) Median  8.40  8.60 Min:Max 2.3:19.2  2.4:20.8 Month 6 endpoint (LOCF) Number 378 385 Mean (SD) 7.25 (2.56)  7.21 (2.40) Median  6.80  6.90 Min:Max  2.4:18.2  2.7:17.6Change from baseline to Month 6 endpoint (LOCF) Number 378 385 Mean (SD) −1.47 (3.10)  −1.69 (3.21) Median  −1.40  −1.70 Min:Max  −13.7:11.3 −12.5:9.0 LS Mean (SE)^(a)  −1.29 (0.191)  −1.39 (0.191) 95% Cl (−1.661to −0.910) (−1.763 to −1.012) LS Mean difference (SE) vs.  0.10 (0.171)Lantusa 95% Cl (−0.234 to 0.437) FPG = Fasting Plasma Glucose LOCF =Last observation carried forward. ^(a)Analysis of covariance (ANCOVA)model with treatment groups (HOE901-U300 and LANTUS), randomizationstrata of screening HbA1c (<8.0, ≥8.0%), and country as fixed effectsand baseline FPG value as a covariate.

1.2.3.3 Eight-Point SMPG Profile

FIG. 3 Describes the Mean 8-Point SMPG Profile (Mmol/l) at Baseline andMonth 6 Endpoint—mITT Population

1.2.3.4 Basal and Mealtime Insulin Dose

FIG. 4 Describes the Average Daily Basal Insulin and Mealtime InsulinDose (U) by Visit During the Main 6-Month On-Treatment Period—mITTPopulation

1.3 SAFETY EVALUATION

1.3.1 Extent of Exposure

TABLE 11 Exposure to investigational product for the main 6-monthon-treatment period - Safety population HOE901-U300 Lantus (N = 404) (N= 402) Cumulative exposure to main 6-month treatment (patient years)194.7 193.3 Duration of main 6-month study treatment (days) Number 404401 Mean (SD) 176.0 (29.8) 176.0 (30.0) Median 183.0 183.0 Min:Max 6:1995:216 Duration of main 6-month study treatment by category [n(%)] up to2 weeks  2 (0.5%)  5 (1.2%)  >2 to 4 weeks  3 (0.7%)  3 (0.7%)  >4 to 8weeks  8 (2.0%)  2 (0.5%)  >8 to 12 weeks  5 (1.2%)  6 (1.5%) >12 to 17weeks  2 (0.5%)  3 (0.7%) >17 to 26 weeks 129 (31.9%) 122 (30.4%) >26weeks 255 (63.1%) 260 (64.8%) Cumulative duration of main 6-month studytreatment by category [n(%)]  ≥1 days 404 (100%) 401 (100%)  >2 weeks402 (99.5%) 396 (98.8%)  >4 weeks 399 (98.8%) 393 (98.0%)  >8 weeks 391(96.8%) 391 (97.5%) >12 weeks 386 (95.5%) 385 (96.0%) >17 weeks 384(95.0%) 382 (95.3%) >26 weeks 255 (63.1%) 260 (64.8%) Note: Patients areconsidered in the treatment group they actually received atrandomization

1.3.2 Hypoglycemia

TABLE 12 Number (%) of patients with at least one emergent hypoglycemiaevent during the main 6-month on-treatment period - Safety populationNocturnal hypoglycemia All hypoglycemia (00:00-05:59) Type ofhypoglycemia event HOE901-U300 Lantus HOE901-U300 Lantus n(%) (N = 404)(N = 402) (N = 404) (N = 402) Any hypoglycemia event 336 (83.2%) 356(88.6%) 183 (45.3%) 238 (59.2%) Severe hypoglycemia  21 (5.2%)  23(5.7%)  8 (2.0%)  10 (2.5%) Documented symptomatic hypoglycemia ≤3.9mmol/L (70 mg/dL) 282 (69.8%) 312 (77.6%) 145 (35.9%) 193 (48.0%) <3.0mmol/L (54 mg/dL) 157 (38.9%) 171 (42.5%)  55 (13.6%)  73 (18.2%)Asymptomatic hypoglycemia ≤3.9 mmol/L (70 mg/dL) 255 (63.1%) 271 (67.4%) 84 (20.8%) 100 (24.9%) <3.0 mmol/L (54 mg/dL)  70 (17.3%)  73 (18.2%) 9 (2.2%)  15 (3.7%) Probable symptomatic  18 (4.5%)  28 (7.0%)  6(1.5%)  9 (2.2%) hypoglycemia Relative hypoglycemia >3.9 mmol/L (70mg/dL)  56 (13.9%)  76 (18.9%)  15 (3.7%)  33 (8.2%) Severe and/orconfirmed^(a) hypoglycemia ≤3.9 mmol/L (70 mg/dL) 329 (81.4%) 352(87.6%) 180 (44.6%) 229 (57.0%) <3.0 mmol/L (54 mg/dL) 185 (45.8%) 202(50.2%)  65 (16.1%)  84 (20.9%) n (%) = number and percentage ofpatients with at least one hypoglycemia event ^(a)Confirmed hypoglycemia= documented symptomatic hypoglycemia or asymptomatic hypoglycemia

Hypoglycemia events are categorized as follows (American DiabetesAssociation Workgroup on Hypoglycemia. Defining and ReportingHypoglycemia in Diabetes. Diabetes Care 2005; 28:1245-49):

Severe Hypoglycemia

Severe hypoglycemia is an event requiring assistance of another personto actively administer carbohydrate, glucagon, or other resuscitativeactions.

These episodes may be associated with sufficient neuroglycopenia toinduce seizure, unconsciousness or coma. Plasma glucose measurements maynot be available during such an event, but neurological recoveryattributable to the restoration of plasma glucose to normal isconsidered sufficient evidence that the event was induced by a lowplasma glucose concentration.

The definition of severe symptomatic hypoglycemia includes all episodesin which neurological impairment was severe enough to preventself-treatment and which were thus thought to place patients at risk forinjury to themselves or others.

Note that “requires assistance” means that the patient could not helphimself or herself. Assisting a patient out of kindness, when assistanceis not required, should not be considered a “requires assistance”incident.

Severe symptomatic hypoglycemia will be qualified as an SAE only if itfulfills SAE criteria. All events of seizure, unconsciousness or comamust be reported as SAEs.

Documented Symptomatic Hypoglycemia

Documented symptomatic hypoglycemia is an event during which typicalsymptoms of hypoglycemia accompanied by a measured plasma glucoseconcentration of ≤70 mg/dL (3.9 mmol/L) (American Diabetes AssociationWorkgroup on Hypoglycemia. Defining and Reporting Hypoglycemia inDiabetes. Diabetes Care 2005; 28:1245-49).

Clinical symptoms that are considered to result from a hypoglycemicepisode are, eg, increased sweating, nervousness, asthenia/weakness,tremor, dizziness, increased appetite, palpitations, headache, sleepdisorder, confusion, seizures, unconsciousness, coma.

Asymptomatic Hypoglycemia

Asymptomatic hypoglycemia is an event not accompanied by typicalsymptoms of hypoglycemia but with a measured plasma glucoseconcentration less than or equal to 70 mg/dL (3.9 mmol/L);

Probable Symptomatic Hypoglycemia

Probable symptomatic hypoglycemia is an event during which symptoms ofhypoglycemia are not accompanied by a plasma glucose determination, butwas presumably caused by a plasma glucose concentration less than orequal to 70 mg/dL (3.9 mmol/L); symptoms treated with oral carbohydratewithout a test of plasma glucose.

Relative Hypoglycemia

Relative hypoglycemia is an event during which the person with diabetesreports any of the typical symptoms of hypoglycemia, and interprets thesymptoms as indicative of hypoglycemia, but with a measured plasmaglucose concentration greater than 70 mg/dL (3.9 mmol/L).

Nocturnal Hypoglycemia

Nocturnal hypoglycemia is any hypoglycemia of the above categories thatoccurs between 00:00 and 05:59 hours. Note: Relative nocturnalhypoglycemia will not be included in the analysis of the main secondaryendpoint (patients with at least one nocturnal hypoglycemia).

In addition of the threshold of less than or equal to 70 mg/dL (3.9mmol/L), hypoglycemia episodes with a plasma glucose of <54 mg/dL (3.0mmol/L) will be analyzed separately (Guideline on clinical investigationof medicinal products in the treatment of diabetes mellitus. Draft. EMA,20 Jan. 2010).

The classification of hypoglycemia will be done on basis of the clocktime: Hypoglycemia episodes will be analyzed by their diurnaldistribution (0:00-24:00) and in addition by time of the day:

-   -   nocturnal hypoglycemia defined by time of the day: any        hypoglycemia of the above categories that occurs between 00:00        and 05:59 a.m. hours, regardless whether patient was awake or        woke up because of the event);    -   daytime hypoglycemia: any hypoglycemia of the above categories        that occurs between 6:00 a.m. and 23:59.

Patients will be instructed to measure finger stick plasma glucoselevels prior to the administration of carbohydrates whenever symptomatichypoglycemia is suspected, unless safety considerations necessitateimmediate glucose rescue prior to confirmation, and then a glucosemeasurement should be performed as soon as safe, with appropriate diarydocumentation.

Details on hypoglycemia episodes will be captured in the patientdiaries, and patients will contact the sites as soon as possiblefollowing severe events to review the details and decide on anynecessary measures to be taken.

All hypoglycemia episodes will be documented on the “hypoglycemiaspecific form” in the e-CRF. This includes all symptomatic hypoglycemiaevents and asymptomatic hypoglycemia. Hypoglycemia events fulfilling thecriteria of a SAE will be documented on the SAE form in the e-CRF.

Incidences of hypoglycemia per patient year will be computed per patientas: 365.25×(number of episodes of hypoglycemia)/(number of days exposed)and summarized by type of event and treatment group.

TABLE 13 Number (%) of patients with at least one emergent hypoglycemiaevent during the main 6-month on-treatment period by study period -Safety population Nocturnal hypoglycemia All hypoglycemia (00:00-05:59)Type of hypoglycemia event HOE901-U300 Lantus HOE901-U300 Lantus n(%) (N= 404) (N = 402) (N = 404) (N = 402) Any hypoglycemia event Overall 336(83.2%) 356 (88.6%) 183 (45.3%) 238 (59.2%) Treatment Start to Week 8275 (68.1%) 310 (77.1%) 112 (27.7%) 153 (38.1%) After Week 8 to Month 6298 (73.8%) 304 (75.6%) 140 (34.7%) 181 (45.0%) Severe hypoglycemiaOverall  21 (5.2%)  23 (5.7%)  8 (2.0%)  10 (2.5%) Treatment Start toWeek 8  7 (1.7%)  12 (3.0%)  3 (0.7%)  3 (0.7%) After Week 8 to Month 6 19 (4.7%)  13 (3.2%)  5 (1.2%)  7 (1.7%) Documented symptomatichypoglycemia ≤3.9 mmol/L (70 mg/dL) Overall 282 (69.8%) 312 (77.6%) 145(35.9%) 193 (48.0%) Treatment Start to Week 8 210 (52.0%) 250 (62.2%) 79 (19.6%) 109 (27.1%) After Week 8 to Month 6 242 (59.9%) 242 (60.2%)108 (26.7%) 146 (36.3%) <3.0 mmol/L (54 mg/dL) Overall 157 (38.9%) 171(42.5%)  55 (13.6%)  73 (18.2%) Treatment Start to Week 8  96 (23.8%)113 (28.1%)  31 (7.7%)  39 (9.7%) After Week 8 to Month 6 119 (29.5%)115 (28.6%)  40 (9.9%)  47 (11.7%) Asymptomatic hypoglycemia ≤3.9 mmol/L(70 mg/dL) Overall 255 (63.1%) 271 (67.4%)  84 (20.8%) 100 (24.9%)Treatment Start to Week 8 187 (46.3%) 210 (52.2%)  44 (10.9%)  60(14.9%) After Week 8 to Month 6 203 (50.2%) 206 (51.2%)  57 (14.1%)  64(15.9%) <3.0 mmol/L (54 mg/dL) Overall  70 (17.3%)  73 (18.2%)  9 (2.2%) 15 (3.7%) Treatment Start to Week 8  34 (8.4%)  39 (9.7%)  6 (1.5%)  10(2.5%) After Week 8 to Month 6  52 (12.9%)  46 (11.4%)  4 (1.0%)  6(1.5%) Severe and/or confirmed^(a) hypoglycemia ≤3.9 mmol/L (70 mg/dL)Overall 329 (81.4%) 352 (87.6%) 180 (44.6%) 229 (57.0%) Treatment Startto Week 8 269 (66.6%) 299 (74.4%) 107 (26.5%) 139 (34.6%) After Week 8to Month 6 295 (73.0%) 303 (75.4%) 135 (33.4%) 180 (44.8%) <3.0 mmol/L(54 mg/dL) Overall 185 (45.8%) 202 (50.2%)  65 (16.1%)  84 (20.9%)Treatment Start to Week 8 117 (29.0%) 131 (32.6%)  38 (9.4%)  48 (11.9%)After Week 8 to Month 6 148 (36.6%) 146 (36.3%)  44 (10.9%)  51 (12.7%)n (%) = number and percentage of patients with at least one hypoglycemiaevent ^(a)Confirmed hypoglycemia = documented symptomatic hypoglycemiaor asymptomatic hypoglycemia

1.3.3 Treatment-Emergent Adverse Events

TABLE 14 Treatment emergent adverse events during the main 6-month on-treatment period - Safety population HOE901-U300 Lantus n (%) (N = 404)(N = 402) Patients with any TEAE 222 (55.0%) 215 (53.5%) Patients withany treatment emergent SAE  25 (6.2%)  21 (5.2%) Patients with any TEAEleading to death  1 (0.2%)  2 (0.5%) Patients with any TEAE leading to 6 (1.5%)  7 (1.7%) permanent treatment discontinuation TEAE: Treatmentemergent adverse event, SAE: Serious Adverse Event n (%) = number andpercentage of patients with at least one TEAE

TABLE 15 Number (%) of patients with TEAE(s) that occurred with HLT ≥ 2%in any treatment group by Primary SOC, HLT and PT for the main 6-monthon-treatment period - Safety population PRIMARY SYSTEM ORGAN CLASS HLT:High Level Term HOE901-U300 Lantus Preferred Term n(%) (N = 404) (N =402) Any class 222 (55.0%) 215 (53.5%) INFECTIONS AND INFESTATIONS 115(28.5%) 121 (30.1%) HLT: Abdominal and gastrointestinal  6 (1.5%)  12(3.0%) infections Abdominal wall abscess  1 (0.2%)  0 Diverticulitis  0 3 (0.7%) Enteritis infectious  1 (0.2%)  0 Gastroenteritis  4 (1.0%)  9(2.2%) HLT: Ear infections  3 (0.7%)  9 (2.2%) Ear infection  2 (0.5%) 6 (1.5%) Otitis externa  1 (0.2%)  1 (0.2%) Otitis media  0  2 (0.5%)HLT: Influenza viral infections  8 (2.0%)  9 (2.2%) Influenza  8 (2.0%) 9 (2.2%) HLT: Lower respiratory tract and lung  18 (4.5%)  24 (6.0%)infections Bronchitis  14 (3.5%)  19 (4.7%) Bronchopneumonia  1 (0.2%) 1 (0.2%) Lower respiratory tract infection  1 (0.2%)  0 Pneumonia  2(0.5%)  4 (1.0%) HLT: Upper respiratory tract infections  56 (13.9%)  51(12.7%) Acute sinusitis  0  3 (0.7%) Acute tonsillitis  0  1 (0.2%)Chronic tonsillitis  1 (0.2%)  0 Laryngitis  0  2 (0.5%) Nasopharyngitis 19 (4.7%)  17 (4.2%) Pharyngitis  3 (0.7%)  2 (0.5%) Rhinitis  1 (0.2%) 0 Sinusitis  11 (2.7%)  10 (2.5%) Upper respiratory tract infection  23(5.7%)  19 (4.7%) HLT: Urinary tract infections  10 (2.5%)  12 (3.0%)Cystitis  2 (0.5%)  3 (0.7%) Kidney infection  0  1 (0.2%)Pyelonephritis  0  1 (0.2%) Pyelonephritis acute  0  1 (0.2%) Urinarytract infection  8 (2.0%)  6 (1.5%) HLT: Viral infections NEC  13 (3.2%) 12 (3.0%) Bronchitis viral  1 (0.2%)  0 Gastroenteritis viral  7 (1.7%) 5 (1.2%) Pneumonia viral  0  1 (0.2%) Respiratory tract infection viral 1 (0.2%)  2 (0.5%) Viral infection  3 (0.7%)  2 (0.5%) Viral rhinitis 0  2 (0.5%) Viral upper respiratory tract infection  3 (0.7%)  1 (0.2%)NERVOUS SYSTEM DISORDERS  42 (10.4%)  40 (10.0%) HLT: Headaches NEC  13(3.2%)  11 (2.7%) Headache  12 (3.0%)  10 (2.5%) Sinus headache  1(0.2%)  2 (0.5%) VASCULAR DISORDERS  12 (3.0%)  13 (3.2%) HLT: Vascularhypertensive disorders NEC  8 (2.0%)  10 (2.5%) Hypertension  8 (2.0%) 10 (2.5%) RESPIRATORY, THORACIC AND  32 (7.9%)  32 (8.0%) MEDIASTINALDISORDERS HLT: Breathing abnormalities  10 (2.5%)  4 (1.0%) Dyspnoea  6(1.5%)  2 (0.5%) Dyspnoea exertional  3 (0.7%)  2 (0.5%)Hyperventilation  1 (0.2%)  0 HLT: Upper respiratory tract signs and  10(2.5%)  7 (1.7%) symptoms Dysphonia  1 (0.2%)  0 Nasal discomfort  0  1(0.2%) Oropharyngeal pain  5 (1.2%)  5 (1.2%) Rhinorrhoea  2 (0.5%)  1(0.2%) Throat irritation  1 (0.2%)  0 Upper respiratory tract congestion 1 (0.2%)  0 GASTROINTESTINAL DISORDERS  54 (13.4%)  48 (11.9%) HLT:Diarrhoea (excl infective)  15 (3.7%)  15 (3.7%) Diarrhoea  15 (3.7%) 15 (3.7%) HLT: Nausea and vomiting symptoms  18 (4.5%)  18 (4.5%)Nausea  15 (3.7%)  11 (2.7%) Vomiting  5 (1.2%)  10 (2.5%)MUSCULOSKELETAL AND CON-  54 (13.4%)  61 (15.2%) NECTIVE TISSUEDISORDERS HLT: Joint related signs and symptoms  11 (2.7%)  16 (4.0%)Arthralgia  8 (2.0%)  14 (3.5%) Joint range of motion decreased  0  2(0.5%) Joint swelling  3 (0.7%)  0 HLT: Musculoskeletal and connective 22 (5.4%)  27 (6.7%) tissue pain and discomfort Back pain  9 (2.2%)  14(3.5%) Flank pain  1 (0.2%)  0 Musculoskeletal chest pain  1 (0.2%)  2(0.5%) Musculoskeletal pain  5 (1.2%)  4 (1.0%) Pain in extremity  7(1.7%)  10 (2.5%) GENERAL DISORDERS AND ADMINIS-  42 (10.4%)  34 (8.5%)TRATION SITE CONDITIONS HLT: Asthenic conditions  12 (3.0%)  8 (2.0%)Asthenia  1 (0.2%)  1 (0.2%) Fatigue  10 (2.5%)  6 (1.5%) Malaise  1(0.2%)  1 (0.2%) HLT: Injection site reactions  9 (2.2%)  6 (1.5%)Injection site discomfort  1 (0.2%)  0 Injection site erythema  0  1(0.2%) Injection site haematoma  4 (1.0%)  3 (0.7%) Injection sitehaemorrhage  0  2 (0.5%) Injection site induration  0  1 (0.2%)Injection site pain  4 (1.0%)  0 Injection site pruritus  1 (0.2%)  0HLT: Oedema NEC  15 (3.7%)  14 (3.5%) Generalised oedema  1 (0.2%)  0Oedema peripheral  14 (3.5%)  14 (3.5%) TEAE: Treatment emergent adverseevent, SOC: System organ class, HLT: High level term, PT: Preferred termMedDRA 15.1 n (%) = number and percentage of patients with at least oneTEAE Note: Table sorted by SOC internationally agreed order and HLT, PTby alphabetic order Only HLT with at least one <HLT ≥ 2%> in at leastone group are presented

1.3.4 Deaths, Serious Treatment-Emergent Adverse Events

1.3.4.1 Death

TABLE 16 Number (%) of patients who died by study period (on study, on-treatment, post-study)- Safety population HOE901-U300 Lantus (N = 404)(N = 402) Death on-study^(a) 3 (0.7%) 3 (0.7%) Death on-study duringfirst 6 months 2 (0.5%) 2 (0.5%) Death on-treatment^(b) 0 2 (0.5%) Deathpost-study^(c) 0 0 TEAE: Treatment emergent adverse event, SAE: Seriousadverse event ^(a)Includes all deaths that occurred after the start oftreatment up to end of study (defined as last protocol planned visit orthe resolution/stabilization of all treatment emergent SAE and adverseevent of pre-specified monitoring) ^(b)On-treatment is main 6-monthon-treatment period ^(c)Includes deaths that occurred after the end ofthe study (as defined in footnote a) and reported in the database

1.3.4.2 Serious Adverse Events

TABLE 17 Number (%) of patients with treatment emergent SAEs by PrimarySOC, HLGT, HLT and PT for the main 6-month on-treatment period - Safetypopulation PRIMARY SYSTEM ORGAN CLASS HLGT: High Level Group Term HLT:High Level Term HOE901-U300 Lantus Preferred Term n(%) (N = 404) (N =402) Any class 25 (6.2%) 21 (5.2%) INFECTIONS AND INFESTATIONS  7 (1.7%) 5 (1.2%) HLGT: Bacterial infectious disorders  1 (0.2%)  1 (0.2%) HLT:Bacterial infections NEC  0  1 (0.2%) Cellulitis  0  1 (0.2%) HLT:Streptococcal infections  1 (0.2%)  0 Erysipelas  1 (0.2%)  0 HLGT:Infections - pathogen unspecified  6 (1.5%)  5 (1.2%) HLT: Abdominal andgastrointestinal  0  1 (0.2%) infections Diverticulitis  0  1 (0.2%)HLT: Bone and joint infections  2 (0.5%)  1 (0.2%) Osteomyelitis  2(0.5%)  1 (0.2%) HLT: Cardiac infections  1 (0.2%)  0 Endocarditis  1(0.2%)  0 HLT: Infections NEC  1 (0.2%)  0 Groin abscess  1 (0.2%)  0HLT: Lower respiratory tract and lung  2 (0.5%)  2 (0.5%) infectionsBronchitis  1 (0.2%)  0 Bronchopneumonia  1 (0.2%)  0 Pneumonia  0  2(0.5%) HLT: Sepsis, bacteraemia, viraemia and  1 (0.2%)  1 (0.2%)fungaemia NEC Sepsis  1 (0.2%)  1 (0.2%) Septic embolus  1 (0.2%)  0HLT: Urinary tract infections  0  1 (0.2%) Pyelonephritis acute  0  1(0.2%) NEOPLASMS BENIGN, MALIGNANT  3 (0.7%)  1 (0.2%) AND UNSPECIFIED(INCL CYSTS AND POLYPS) HLGT: Breast neoplasms malignant and  1 (0.2%) 0 unspecified (incl nipple) HLT: Breast and nipple neoplasms malignant 1 (0.2%)  0 Breast cancer  1 (0.2%)  0 HLGT: Leukaemias  0  1 (0.2%)HLT: Leukaemias chronic myeloid  0  1 (0.2%) Chronic myeloid leukaemia 0  1 (0.2%) HLGT: Reproductive neoplasms male  1 (0.2%)  0 malignantand unspecified HLT: Prostatic neoplasms malignant  1 (0.2%)  0 Prostatecancer  1 (0.2%)  0 HLGT: Respiratory and mediastinal neo-  1 (0.2%)  0plasms malignant and unspecified HLT: Respiratory tract and pleuralneoplasms  1 (0.2%)  0 malignant cell type unspecified NEC Metastaticbronchial carcinoma  1 (0.2%)  0 METABOLISM AND NUTRITION  1 (0.2%)  3(0.7%) DISORDERS HLGT: Electrolyte and fluid balance  0  1 (0.2%)conditions HLT: Potassium imbalance  0  1 (0.2%) Hyperkalaemia  0  1(0.2%) HLGT: Glucose metabolism disorders  1 (0.2%)  2 (0.5%) (incldiabetes mellitus) HLT: Diabetes mellitus (incl subtypes)  0  1 (0.2%)Diabetes mellitus inadequate control  0  1 (0.2%) HLT: Hypoglycaemicconditions NEC  1 (0.2%)  1 (0.2%) Hypoglycaemia  1 (0.2%)  1 (0.2%)PSYCHIATRIC DISORDERS  0  1 (0.2%) HLGT: Depressed mood disorders and  0 1 (0.2%) disturbances HLT: Depressive disorders  0  1 (0.2%) Depression 0  1 (0.2%) NERVOUS SYSTEM DISORDERS  3 (0.7%)  2 (0.5%) HLGT: Centralnervous system vascular  1 (0.2%)  0 disorders HLT: Transientcerebrovascular events  1 (0.2%)  0 Transient ischaemic attack  1 (0.2%) 0 HLGT: Neurological disorders NEC  2 (0.5%)  1 (0.2%) HLT:Disturbances in consciousness NEC  2 (0.5%)  1 (0.2%) Hypoglycaemicunconsciousness  2 (0.5%)  0 Syncope  0  1 (0.2%) HLGT: Peripheralneuropathies  0  1 (0.2%) HLT: Acute polyneuropathies  0  1 (0.2%)Guillain-Barre syndrome  0  1 (0.2%) CARDIAC DISORDERS  5 (1.2%)  7(1.7%) HLGT: Cardiac arrhythmias  1 (0.2%)  2 (0.5%) HLT: Cardiacconduction disorders  0  1 (0.2%) Bundle branch block left  0  1 (0.2%)HLT: Supraventricular arrhythmias  0  1 (0.2%) Atrial fibrillation  0  1(0.2%) HLT: Ventricular arrhythmias and cardiac  1 (0.2%)  0 arrestVentricular tachycardia  1 (0.2%)  0 HLGT: Cardiac valve disorders  0  1(0.2%) HLT: Aortic valvular disorders  0  1 (0.2%) Aortic valve stenosis 0  1 (0.2%) HLGT: Coronary artery disorders  4 (1.0%)  3 (0.7%) HLT:Coronary artery disorders NEC  2 (0.5%)  1 (0.2%) Coronary arterydisease  2 (0.5%)  1 (0.2%) HLT: Ischaemic coronary artery disorders  2(0.5%)  2 (0.5%) Acute coronary syndrome  1 (0.2%)  0 Angina pectoris  0 1 (0.2%) Myocardial ischaemia  1 (0.2%)  1 (0.2%) HLGT: Heart failures 0  2 (0.5%) HLT: Heart failures NEC  0  2 (0.5%) Cardiac failure  0  1(0.2%) Cardiac failure chronic  0  1 (0.2%) VASCULAR DISORDERS  0  1(0.2%) HLGT: Arteriosclerosis, stenosis, vascular  0  1 (0.2%)insufficiency and necrosis HLT: Aortic necrosis and vascular  0  1(0.2%) insufficiency Aortic stenosis  0  1 (0.2%) RESPIRATORY, THORACICAND  1 (0.2%)  0 MEDIASTINAL DISORDERS HLGT: Respiratory disorders NEC 1 (0.2%)  0 HLT: Breathing abnormalities  1 (0.2%)  0 Dyspnoeaexertional  1 (0.2%)  0 GASTROINTESTINAL DISORDERS  1 (0.2%)  0 HLGT:Gastrointestinal stenosis and  1 (0.2%)  0 obstruction HLT:Gastrointestinal stenosis and obstruction  1 (0.2%)  0 NEC Ileus  1(0.2%)  0 HEPATOBILIARY DISORDERS  0  1 (0.2%) HLGT: Gallbladderdisorders  0  1 (0.2%) HLT: Cholecystitis and cholelithiasis  0  1(0.2%) Cholelithiasis  0  1 (0.2%) SKIN AND SUBCUTANEOUS TISSUE  1(0.2%)  0 DISORDERS HLGT: Skin and subcutaneous tissue  1 (0.2%)  0disorders NEC HLT: Skin and subcutaneous tissue  1 (0.2%)  0 ulcerationsDiabetic foot  1 (0.2%)  0 MUSCULOSKELETAL AND CONNEC-  2 (0.5%)  2(0.5%) TIVE TISSUE DISORDERS HLGT: Joint disorders  1 (0.2%)  1 (0.2%)HLT: Osteoarthropathies  1 (0.2%)  0 Osteoarthritis  1 (0.2%)  0 HLT:Spondyloarthropathies  0  1 (0.2%) Spondylitis  0  1 (0.2%) HLGT: Muscledisorders  1 (0.2%)  0 HLT: Myopathies  1 (0.2%)  0 Rhabdomyolysis  1(0.2%)  0 HLGT: Musculoskeletal and connective tissue  0  1 (0.2%)disorders NEC HLT: Musculoskeletal and connective tissue  0  1 (0.2%)pain and discomfort Musculoskeletal chest pain  0  1 (0.2%) RENAL ANDURINARY DISORDERS  2 (0.5%)  3 (0.7%) HLGT: Bladder and bladder neckdisorders  1 (0.2%)  0 (excl calculi) HLT: Bladder neoplasms  1 (0.2%) 0 Urinary bladder polyp  1 (0.2%)  0 HLGT: Nephropathies  0  1 (0.2%)HLT: Nephropathies and tubular disorders  0  1 (0.2%) NEC Diabeticnephropathy  0  1 (0.2%) HLGT: Renal disorders (excl nephropathies)  1(0.2%)  2 (0.5%) HLT: Renal failure and impairment  1 (0.2%)  2 (0.5%)Renal failure acute  1 (0.2%)  0 Renal failure chronic  0  2 (0.5%)HLGT: Urolithiases  0  1 (0.2%) HLT: Renal lithiasis  0  1 (0.2%)Nephrolithiasis  0  1 (0.2%) REPRODUCTIVE SYSTEM AND BREAST  1 (0.2%)  0DISORDERS HLGT: Menstrual cycle and uterine bleeding  1 (0.2%)  0disorders HLT: Menstruation and uterine bleeding NEC  1 (0.2%)  0Metrorrhagia  1 (0.2%)  0 GENERAL DISORDERS AND ADMINI-  1 (0.2%)  1(0.2%) STRATION SITE CONDITIONS HLGT: General system disorders NEC  1(0.2%)  1 (0.2%) HLT: Pain and discomfort NEC  1 (0.2%)  1 (0.2%)Non-cardiac chest pain  1 (0.2%)  1 (0.2%) INJURY, POISONING ANDPROCEDURAL  2 (0.5%)  4 (1.0%) COMPLICATIONS HLGT: Bone and jointinjuries  1 (0.2%)  0 HLT: Limb injuries NEC (incl traumatic  1 (0.2%) 0 amputation) Meniscus lesion  1 (0.2%)  0 HLGT: Exposures, chemicalinjuries and  0  1 (0.2%) poisoning HLT: Poisoning and toxicity  0  1(0.2%) Toxicity to various agents  0  1 (0.2%) HLGT: Injuries NEC  1(0.2%)  2 (0.5%) HLT: Cerebral injuries NEC  0  1 (0.2%) Subduralhaematoma  0  1 (0.2%) HLT: Non-site specific injuries NEC  1 (0.2%)  1(0.2%) Fall  1 (0.2%)  1 (0.2%) HLT: Site specific injuries NEC  0  1(0.2%) Head injury  0  1 (0.2%) HLGT: Procedural related injuries and  0 1 (0.2%) complications NEC HLT: Anaesthetic complications  0  1 (0.2%)Airway complication of anaesthesia  0  1 (0.2%) SAE: Serious adverseevent, SOC: System organ class, HLGT: High level group term, HLT: Highlevel term, PT: Preferred term MedDRA 15.1 n (%) = number and percentageof patients with at least one treatment emergent SAE Note: Table sortedby SOC internationally agreed order and HLGT, HLT, PT by alphabeticorder

1.3.5 Adverse Events Leading to Withdrawal

TABLE 18 Number (%) of patients with TEAE(s) leading to permanenttreatment discontinuation by Primary SOC, HLGT, HLT and PT for the main6-month on- treatment period - Safety population PRIMARY SYSTEM ORGANCLASS HLGT: High Level Group Term HLT: High Level Term HOE901-U300Lantus Preferred Term n(%) (N = 404) (N = 402) Any class 6 (1.5%) 7(1.7%) INFECTIONS AND INFESTATIONS 0 2 (0.5%) HLGT: Infections -pathogen unspecified 0 2 (0.5%) HLT: Infections NEC 0 1 (0.2%) Woundinfection 0 1 (0.2%) HLT: Upper respiratory tract infections 0 1 (0.2%)Acute sinusitis 0 1 (0.2%) NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 1(0.2%) 1 (0.2%) (INCL CYSTS AND POLYPS) HLGT: Leukaemias 0 1 (0.2%) HLT:Leukaemias chronic myeloid 0 1 (0.2%) Chronic myeloid leukaemia 0 1(0.2%) HLGT: Respiratory and mediastinal neoplasms malignant 1 (0.2%) 0and unspecified HLT: Respiratory tract and pleural neoplasms malignantcell 1 (0.2%) 0 type unspecified NEC Metastatic bronchial carcinoma 1(0.2%) 0 METABOLISM AND NUTRITION DISORDERS 0 1 (0.2%) HLGT: Glucosemetabolism disorders (incl diabetes mellitus) 0 1 (0.2%) HLT: Diabetesmellitus (incl subtypes) 0 1 (0.2%) Diabetes mellitus inadequate control0 1 (0.2%) PSYCHIATRIC DISORDERS 1 (0.2%) 1 (0.2%) HLGT: Anxietydisorders and symptoms 1 (0.2%) 1 (0.2%) HLT: Anxiety symptoms 1 (0.2%)0 Anxiety 1 (0.2%) 0 HLT: Stress disorders 0 1 (0.2%) Burnout syndrome 01 (0.2%) NERVOUS SYSTEM DISORDERS 0 1 (0.2%) HLGT: Central nervoussystem vascular disorders 0 1 (0.2%) HLT: Central nervous systemhaemorrhages and 0 1 (0.2%) cerebrovascular accidents Cerebral ischaemia0 1 (0.2%) HLGT: Peripheral neuropathies 0 1 (0.2%) HLT: Chronicpolyneuropathies 0 1 (0.2%) Diabetic neuropathy 0 1 (0.2%) CARDIACDISORDERS 1 (0.2%) 2 (0.5%) HLGT: Cardiac arrhythmias 1 (0.2%) 0 HLT:Ventricular arrhythmias and cardiac arrest 1 (0.2%) 0 Ventriculartachycardia 1 (0.2%) 0 HLGT: Coronary artery disorders 0 1 (0.2%) HLT:Ischaemic coronary artery disorders 0 1 (0.2%) Myocardial ischaemia 0 1(0.2%) HLGT: Heart failures 0 1 (0.2%) HLT: Heart failures NEC 0 1(0.2%) Cardiac failure chronic 0 1 (0.2%) RESPIRATORY, THORACIC ANDMEDIASTINAL 0 1 (0.2%) DISORDERS HLGT: Pulmonary vascular disorders 0 1(0.2%) HLT: Pulmonary thrombotic and embolic conditions 0 1 (0.2%)Pulmonary embolism 0 1 (0.2%) MUSCULOSKELETAL AND CONNECTIVE TISSUE 1(0.2%) 1 (0.2%) DISORDERS HLGT: Joint disorders 1 (0.2%) 1 (0.2%) HLT:Osteoarthropathies 1 (0.2%) 0 Osteoarthritis 1 (0.2%) 0 HLT:Spondyloarthropathies 0 1 (0.2%) Spondylitis 0 1 (0.2%) RENAL ANDURINARY DISORDERS 0 1 (0.2%) HLGT: Nephropathies 0 1 (0.2%) HLT:Nephropathies and tubular disorders NEC 0 1 (0.2%) Diabetic nephropathy0 1 (0.2%) HLGT: Renal disorders (excl nephropathies) 0 1 (0.2%) HLT:Renal failure and impairment 0 1 (0.2%) Renal failure chronic 0 1 (0.2%)GENERAL DISORDERS AND ADMINISTRATION SITE 0 1 (0.2%) CONDITIONS HLGT:General system disorders NEC 0 1 (0.2%) HLT: Pain and discomfort NEC 0 1(0.2%) Non-cardiac chest pain 0 1 (0.2%) INVESTIGATIONS 2 (0.5%) 0 HLGT:Metabolic, nutritional and blood gas investigations 1 (0.2%) 0 HLT:Carbohydrate tolerance analyses (incl diabetes) 1 (0.2%) 0 Blood glucosedecreased 1 (0.2%) 0 HLGT: Physical examination and organ system statustopics 1 (0.2%) 0 HLT: Physical examination procedures and organ system1 (0.2%) 0 status Weight increased 1 (0.2%) 0 INJURY, POISONING ANDPROCEDURAL 0 2 (0.5%) COMPLICATIONS HLGT: Exposures, chemical injuriesand poisoning 0 1 (0.2%) HLT: Poisoning and toxicity 0 1 (0.2%) Toxicityto various agents 0 1 (0.2%) HLGT: Procedural related injuries andcomplications NEC 0 1 (0.2%) HLT: Anaesthetic complications 0 1 (0.2%)Airway complication of anaesthesia 0 1 (0.2%) TEAE: Treatment emergentadverse event, SOC: System organ class, HLGT: High level group term,HLT: High level term, PT: Preferred term MedDRA 15.1 n (%) = number andpercentage of patients with at least one TEAE leading to permanenttreatment discontinuation Note: Table sorted by SOC internationallyagreed order and HLGT, HLT, PT by alphabetic order

1.3.6 Other Significant Adverse Events

1.3.6.1 Hypersensitivity Reaction

TABLE 19 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term -Hypersensitivity reactions during the main 6-month on-treatment period -Safety population HOE901-U300 Lantus Preferred Term (N = 404) (N = 402)Any hypersensitivity reactions 3 (0.7%) 2 (0.5%) Blister 2 (0.5%) 2(0.5%) Skin exfoliation 1 (0.2%) 0 Drug eruption 0 1 (0.2%) MedDRA 15.1TEAE: Treatment emergent adverse event n (%) = number and percentage ofpatients with at least one hypersensitivity reaction event

1.3.6.2 Injection Site Reactions

TABLE 20 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term - Injection sitereactions during the main 6-month on-treatment period - Safetypopulation HOE901-U300 Lantus Preferred Term (N = 404) (N = 402) Anyinjection site reaction 9 (2.2%) 6 (1.5%) Injection site haematoma 4(1.0%) 3 (0.7%) Injection site pain 4 (1.0%) 0 Injection site discomfort1 (0.2%) 0 Injection site pruritus 1 (0.2%) 0 Injection site erythema 01 (0.2%) Injection site haemorrhage 0 2 (0.5%) Injection site induration0 1 (0.2%) MedDRA 15.1 TEAE: Treatment emergent adverse event n (%) =number and percentage of patients with at least one local tolerabilityat injection site event

EXAMPLE 2: 6-MONTH, MULTICENTER, RANDOMIZED, OPEN-LABEL, PARALLEL-GROUPSTUDY COMPARING THE EFFICACY AND SAFETY OF A NEW FORMULATION OF INSULINGLARGINE AND LANTUS® BOTH IN COMBINATION WITH ORAL ANTIHYPERGLYCEMICDRUG(S) IN PATIENTS WITH TYPE 2 DIABETES MELLITUS WITH A 6-MONTH SAFETYEXTENSION PERIOD)

Synopsis

Study Center(s):

Multicenter

Phase of Development:

3

Objectives:

Primary Objective: To assess the effects on glycemic control ofHOE901-U300 in comparison to Lantus when given as basal insulin in aregimen with oral antihyperglycemic drug(s) in terms of HbA1c changeover a period of 6 months in patients with type 2 diabetes mellitus.

Main secondary Objectives: To compare HOE901-U300 and Lantus in terms ofoccurrence of nocturnal hypoglycemia, change in preinjection plasmaglucose, and change in variability of preinjection plasma glucose.

Further secondary objectives:

-   -   To compare HOE901-U300 and Lantus in terms of reaching target        HbA_(1c) values and controlled plasma glucose;    -   To compare HOE901-U300 and Lantus in terms of treatment        satisfaction of patients using the Diabetes Treatment        Satisfaction Questionnaire (status) (DTSQs) (not presented in        KRM);    -   To assess the safety and tolerability of HOE901-U300.

Methodology:

The randomization was 1:1 (HOE901-U300 versus Lantus) and was stratifiedaccording to HbA_(1c) values at screening (<8.0%; 8.0%). The sample size(400 with HOE901-U300 and 400 with Lantus) was chosen to ensuresufficient power for the primary endpoint (change in HbA_(1c) frombaseline to endpoint [Month 6]) as well as to allow conclusions on thefirst main secondary endpoint (occurrence of nocturnal hypoglycemia).

Number of Patients:

Planned: 800 (400 per Randomized: 811 Treated: 809 treatment arm)Evaluated: Efficacy: 808 Safety: 809

Diagnosis and Criteria for Inclusion:

Inclusion criteria: Patients with type 2 diabetes mellitus as defined byWHO diagnosed for at least 1 year at the time of the screening visit;signed written informed consent. Key exclusion criteria: Age <18 years;HbA_(1c)<7.0% or >10% at screening; diabetes other than type 2 diabetesmellitus; Less than 6 months on basal insulin treatment together withoral antihyperglycemic drugs and self-monitoring of blood glucose; totaldaily dose insulin glargine <42 U or equivalent dose of NPH in the last4 weeks prior to the study (if NPH was used as basal insulin prior tothe study).

Study Treatments

Investigational Medicinal Products:

Tested drug: HOE901-U300; Control drug: Lantus

Formulations:

HOE901-U300 (insulin glargine 300 U/mL solution) is a sterile,non-pyrogenic, clear, colorless solution in a glass cartridge that hasbeen assembled in a pen-injector (prefilled ie, disposable pen). Lantus(insulin glargine 100 U/mL solution) is a sterile, non-pyrogenic, clear,colorless solution supplied in the marketed Solostar® (prefilled ie,disposable pen).

Route of Administration:

subcutaneous injection

Dose Regimen:

Once daily injection in the evening. The injection time was fixed at thetime of randomization and was to be maintained for the duration of thestudy.

Starting Dose:

Patients on Lantus or NPH once daily prior to the baseline visit: thedaily dose (U) of HOE901-U300 or Lantus was equal to the median of thetotal daily basal insulin doses in the last 3 days prior to the baselinevisit.

Patients on NPH more than once daily prior to the baseline visit: thedaily dose of for HOE901-U300 or Lantus (U) was to be approximately 20%less than the median of the total daily NPH insulin doses in the last 3days prior to the baseline visit.

The basal insulin dose was adjusted once weekly to achieve fasting SMPGin the target range of 80 to 100 mg/dL (4.4 to 5.6 mmol/L):

-   -   by +3 U, if the median fasting SMPG of last 3 days was in the        range of >100 mg/dL and <140 mg/dL (>5.6 and <7.8 mmol/L)    -   by +6 U, if the median fasting SMPG of last 3 days was 140 mg/dL        7.8 mmol/L)    -   by −3 U, if the median fasting SMPG of last 3 days was in the        range of 60 mg/dL and <80 mg/dL 3.3 and <4.4 mmol/L).

Rescue Treatment:

If the basal insulin adjustment failed to decrease FPG/HbA1c under thethreshold values of 11.1 mmol/L (200 mg/dL) for FPG and 8% for HbA1c atweek 12 or later and no apparent reason for insufficient control wasidentified, intensification of the treatment was to be considered. Thechoice of the anti-diabetic treatment to be added to the basal insulinand oral antihyperglycemic background therapy was based onInvestigator's decision and local labeling documents.

Noninvestigational Medicinal Products:

Patients in both treatment groups were to continue with their oralantihyperglycemic background therapy at a stable dose during the study,except sulfonylurea which were prohibited within 2 months before thescreening visit and during the study. Rescue therapy was also consideredas non investigational medicinal product.

Duration of Treatment:

Up to 12 months

Duration of Observation:

up to 58 weeks (up to 2-week screening period+6-month efficacy andsafety period+6-month safety extension period+a 4-week post-treatmentfollow up period)

The analysis period for efficacy and safety is the main 6-monthon-treatment period. Results presented in the present KRM refer to thisperiod.

For all patients requiring rescue therapy during the 6-month treatmentperiod, the last post-baseline efficacy measurement before the start ofrescue therapy was used as the efficacy endpoint. These patients wereexcluded from efficacy analyses after initiation of rescue treatment.For safety endpoints; the analysis period is the main 6-monthon-treatment period regardless of the use of rescue therapy.

Criteria for Evaluation:

Efficacy:

Primary Efficacy Endpoint:

change in HbA_(1c) from baseline to endpoint (Month 6).

Main Secondary Endpoints:

incidence of patients (%) with at least one nocturnal hypoglycemiabetween start of Week 9 and endpoint (month 6), indicated as severeand/or confirmed by plasma glucose ≤70 mg/dL (3.9 mmol/L); change inpreinjection SMPG from baseline to endpoint (Month 6) and change invariability of preinjection SMPG from baseline to endpoint (Month 6).

Safety:

Hypoglycemia, occurrence of adverse events particularlytreatment-emergent adverse events (TEAEs) and serious adverse events(SAEs), TEAEs leading to withdrawal and TEAEs leading to death,injection site reactions and hypersensitivity reactions. Followinginformation not presented in this KRM: physical examination, othersafety information including clinical laboratory data, vital signs,12-lead ECG and anti-insulin antibodies.

Following information not presented in this KRM: physical examination,other safety information including clinical laboratory data, vitalsigns, 12-lead ECG and anti-insulin antibodies.

Statistical Methods:

The primary efficacy endpoint (change in HbA_(1c) from baseline toendpoint [Month 6]) was analyzed using an analysis of covariance(ANCOVA) model with treatment, strata of screening HbA_(1c) (<8.0 and≥8.0%), and country as fixed effects and using the HbA_(1c) baselinevalue as a covariate. Differences between HOE901-U300 and Lantus andtwo-sided 95% confidence intervals were estimated within the frameworkof ANCOVA.

A stepwise closed testing approach was used for the primary efficacyendpoint to assess non-inferiority and superiority sequentially. Step 1assessed non inferiority of HOE901-U300 versus Lantus. To assessnon-inferiority, the upper bound of the two sided 95% CI for thedifference in the mean change in HbA1c from baseline to endpoint betweenHOE901-U300 and Lantus was compared with a predefined non inferioritymargin of 0.4% for HbA1c. Non-inferiority would be demonstrated if theupper bound of the two-sided 95% CI of the difference betweenHOE901-U300 and Lantus on mITT population is <0.4%. Step 2 assessedsuperiority of HOE901-U300 versus Lantus only if non inferiority wasdemonstrated. The superiority of HOE901-U300 over Lantus wasdemonstrated if the upper bound of the two-sided 95% CI of thedifference between HOE901-U300 and Lantus on mITT population was <0.

Only if non-inferiority of HOE901-U300 versus Lantus had beendemonstrated for the primary endpoint, would testing for superiority ofHOE901-U300 over Lantus on the main secondary endpoints occur within theframe of a hierarchical testing procedure. Safety analyses weredescriptive, based on the safety population.

Summary:

Population Characteristics:

A total of 811 patients with type 2 diabetes mellitus were randomized toHOE901-U300 (n=404) or to Lantus (n=407); 809 patients were exposed toIMP (safety population). The mITT population (efficacy population)included 808 patients.

Overall, a comparable number of patients in each treatment groupdiscontinued the study treatment prematurely (HOE901-U300: 36/404, 8.9%;Lantus 38/407, 9.3%). A total of 344 (85.1%) patients in the HOE901-U300arm and 349 (85.7%) in the Lantus arm completed the main 6-monthtreatment period (patients who received rescue medication were excludedfrom the completers population).

Demographics and baseline characteristics were well-balanced between thetreatment groups. The mean age of the study population was 58.2 years,190/811 (23.4%) were 65 years. The mean BMI at baseline was 34.8 kg/m².There were slightly more patients with a BMI above 40 kg/m² in theHOE901-U300 group (21.5%) than in the Lantus group (16.7%). The meanduration of diabetes prior to study start was 12.6 years; the meanduration of prior treatment with basal insulin was 3.8 years. Themajority of patients took insulin glargine (78.8% vs. NPH 21.2%) on the7 days before start of study treatment; more patients from the Lantusgroup were on insulin glargine (82.8%) compared to the HOE901-U300 group(74.9%). The median daily basal insulin dose at baseline was 0.614 U/kgbody weight.

Mean HbA1c at baseline was similar in both treatment groups(HOE901-U300: 8.28% and Lantus: 8.22%; for evaluable patients, i.e. whohad a baseline and at least one post-baseline HbA1c assessment).

Efficacy Results:

Primary Endpoint:

The LS mean change in HbA1c from baseline to endpoint (Month 6) wassimilar in both treatment groups (HOE901-U300: −0.57% (95% CI [−0.756;−0.387]); Lantus: −0.56% (95% CI [−0.744; −0.379]). Non-inferiority ofHOE901-U300 versus Lantus was demonstrated with the LS mean differencein HbA1c versus Lantus of −0.01% (95% CI [−0.139; 0.119]) with the upperbound lower than the predefined non-inferiority margin of 0.4%.Non-inferiority was also the case with the non-inferiority margin of0.3%. Superiority of HOE901-U300 versus Lantus was not demonstrated.

1st Main Secondary Endpoint:

The incidence of patients with at least one nocturnal severe and/orconfirmed hypoglycemia between start of Week 9 and Month 6 was lower inthe HOE901-U300 group [87/403 (21.6%)] than in the Lantus group [113/405(27.9%)]. Superiority of HOE901-U300 versus Lantus was shown with arelative risk of 0.77 (95% CI [0.61, 0.99]) (p=0.0380).

2nd Main Secondary Endpoint:

The LS mean change in pre-injection SMPG from baseline to endpoint(Month 6) was similar in the HOE901-U300 (−0.56 mmol/L) and Lantusgroups (−0.51 mmol/L). The difference between the treatment groups wasnot statistically significant (LS mean difference −0.04 (95% CI [−0.438,0.350], p=0.8279).

3rd Main Secondary Endpoint:

As the superiority of HOE901-U300 versus Lantus was not demonstrated forthe second main secondary endpoint, no further test was performed forthe third main secondary endpoint (decrease in variability ofpre-injection SMPG at Month 6, which was numerically larger in theHOE901-U300 group (−2.34) compared to the Lantus group (−0.53).

Other Secondary Efficacy Endpoints (Month 6):

The proportion of patients having reached HbA1c<7% was similar betweentreatment groups (30.6% in the HOE901-U300; 30.4% in the Lantus). Forthe mean change in FPG, a similar decrease was shown for the twotreatment groups. Graphical presentation of the 8-point SMPG profilesshowed in both treatment groups a comparable, marked decrease in plasmaglucose at endpoint (Month 6) compared with baseline.

At month 6, the mean daily insulin dose in the HOE901-U300 group was 91U (0.92 U/kg) and 82 U (0.84 U/kg) in the Lantus group.

A similar number of patients in both treatment groups received a rescuetherapy during the main 6-month treatment period (5.7% for HOE901-U300,4.9% for Lantus.

Safety Results:

Overall, hypoglycemia was reported by a consistently lower percentage ofpatients in the HOE901-U300 group than in the Lantus group. Thisdifference was even more pronounced during the first 2 months of studytreatment as well as for events of nocturnal hypoglycemia. During themain 6-month on-treatment period severe hypoglycemia was reported in4/403 (1%) of HOE901-U300 treated patients and 6/406 (1.5%) of Lantustreated patients.

The percentages of patients with any TEAEs (HOE901-U300, 236/403[58.6%]; Lantus: 206/406 [50.7%]) was higher for the patients in theHOE901-U300 treatment group than in the Lantus group, with no specificSOC contributing. Serious TEAEs were reported by a similar number ofpatients in both treatment groups (HOE901-U300, 15 [3.7%]; Lantus, 15[3.7%]).

Two (0.5%) patients in the HOE901-U300 and 1 (0.2%) patient in theLantus treatment group died during the 6-months on-treatment period.

The events with fatal outcome in the two patients in the HOE901-U300group included myocardial infarction and sudden cardiac death due toadvanced coronary artery disease. Both patients suffered frompre-existing significant cardiovascular pathology and had multiple riskfactors contributing to the fatal outcome. The patient in the Lantusgroup experienced exacerbation of chronic pyelonephritis with fataloutcome. None of the deaths occurred during the 6 months treatmentperiod were considered related to study drug.

A similar number of patients in both treatment groups experienced TEAEsleading to permanent treatment discontinuation (HOE901-U300: n=6, 1.5%;Lantus: n=4, 1.0%).

Hypersensitivity reactions during the main 6-month on-treatment periodwere reported at a similar rate in both treatment groups (HOE901-U300:n=13, 3.2%; Lantus: n=16, 3.9%).

Overall injection site reactions during the main 6-month on-treatmentperiod showed higher rate of reporting in the Lantus treatment groupthan in the HOE901-U300 group (Lantus: n=12, 3.0%; HOE901-U300: n=4,1.0%).

In both treatment groups, there was no apparent change in body weight(0.08 kg for HOE901-U300 and 0.66 kg for Lantus).

Conclusions:

In this study in 811 patients with T2DM on basal insulin in combinationwith oral antidiabetic drug(s), the baseline characteristics anddemographic characteristics were well balanced across treatment groups.Non-inferiority of HOE901-U300 versus Lantus was shown for the primaryefficacy endpoint (change in HbA1c from baseline to endpoint [Month 6]).The incidence of patients (%) reporting nocturnal hypoglycemia (severeand/or confirmed by SMPG ≤70 mg/dL [3.9 mmol/L]) between start of Week 9and Month 6 was significantly lower in the HOE901-U300 group than in theLantus group (21.6% and 27.9% respectively, RR of 0.77, p-value 0.0380;1st main secondary efficacy endpoint). Comparable results between thetreatment groups were found for the other secondary endpoints ofpre-injection plasma glucose, variability of pre-injection plasmaglucose, number of patients reaching target HbA1c and mean change ofFPG, change of 8-point SMPG profile and variability of 24-hour averageplasma glucose.

Overall incidence of hypoglycemia (% of patients with at least oneevent) during the main 6-month on-treatment period was consistentlylower in the HOE901-U300 group than in the Lantus group regardless ofthe category of hypoglycemia. This difference in favor of HOE901-U300was even more pronounced for nocturnal hypoglycemia of all categories.

HOE901-U300 was well tolerated during the main 6-month on-treatmentperiod of the study and no specific safety concerns were observed.

Summary of the efficacy and safety results of the twelve month EDITION 2extension study

-   -   HbA1c: during the safety extension period (from the main study        endpoint [Month 6] to the End of Treatment [Month 12]) HbA1c        remained stable and was comparable in both treatment groups    -   rescue: during the whole treatment period, the percentages of        patients requiring a rescue therapy was similar in both        treatment groups (8.2% for HOE901-U300, 10.1% for Lantus).        During the 6-month safety extension period rescue therapy was        started in lower percentage of patients in the HOE901-U300        treatment group than in the Lantus group (2.5% for HOE901-U300,        5.4% for Lantus)    -   hypoglycemia: overall, similarly as during the main 6-month        treatment period, during the whole study on-treatment period        hypoglycemia occurred in a lower percentage of patients in the        HOE901-U300 group than in the Lantus, regardless of category of        hypoglycemia    -   safety: HOE901-U300 was well tolerated during the study and no        specific safety concerns were observed; during the whole        treatment period, the percentages of patients with any TEAEs was        higher for the patients in the HOE901-U300 treatment group than        in the Lantus group (278/403 [69.0%] and 244/406 [60.1%],        respectively), with no specific SOC contributing. Serious TEAEs        were reported by a similar number of patients (30 [7.4%]) in        both treatment groups. Four (1.0%) patients in the HOE901-U300        and 2 (0.5%) patient in the Lantus treatment group had TEAE        leading to death during the whole study on-treatment period    -   body weight: in both treatment groups, during the whole study        on-treatment period there was small increase in body weight        (0.41 kg for HOE901-U300 and 1.15 kg for Lantus).

2 Results

2.1 Study Patients

2.1.1 Study Disposition

TABLE 21 Patient disposition—Randomized population HOE901-U300 Lantus (N= 404) (N = 407) Randomized and treated 403 (99.8%) 406 (99.8%)Completed main 6-month treatment period 344 (85.1%) 349 (85.7%)Permanently discontinued the treatment 36 (8.9%) 38 (9.3%) during themain 6-month period ^(a) Rescue intake during the 23 (5.7%) 20 (4.9%)main 6-month period Subject's request for 24 (5.9%) 23 (5.7%) treatmentdiscontinuation Reason for treatment discontinuation during the main6-month period Adverse event 6 (1.5%) 4 (1.0%) Lack of efficacy 2 (0.5%)0 Poor compliance to protocol 4 (1.0%) 4 (1.0%) Other reasons 24 (5.9%)30 (7.4%) Status at last study contact of patients who permanentlydiscontinued the treatment during the main 6-month period Alive 34(8.4%) 35 (8.6%) Dead 2 (0.5%) 1 (0.2%) Note: percentages are calculatedusing the number of patients randomized as denominator Patients whocompleted the main 6-month treatment period are patients who did notpermanently discontinue study treatment and who did not take any rescuemedication ^(a) Two subjects in the Lantus arm had their study statusafter the cut-off date

TABLE 22 Analysis populations HOE901-U300 Lantus All Randomizedpopulation 404 (100%) 407 (100%) 811 (100%) Efficacy populationsModified Intent-to-Treat 403 (99.8%) 405 (99.5%) 808 (99.6%) (mITT)Month 6 completers 344 (85.1%) 349 (85.7%) 693 (85.5%) Safety population403 406 809 Note: For the safety population, patients are tabulatedaccording to treatment actually received (as treated) For the otherpopulations, patients are tabulated according to their randomizedtreatment

TABLE 23 Number (%) of patients requiring rescue therapy during the main6-month on-treatment period-miTT population HOE901-U300 Lantus (N = 403)(N = 405) Rescue medication Number 403 405 n (%) 23 (5.7%) 20 (4.9%) RR(95% Cl) vs. Lantus ^(a) 1.16 (0.65 to 2.07) — RR = relative risk ^(a)Based on RR stratified by randomization strata of screening HbA1c (<8.0or ≥8.0%)., using a CHM methodology

2.1.2 Demographics and Baseline Characteristics

TABLE 24 Demographics and patient characteristics at baseline—Randomizedpopulation HOE901- U300 Lantus All (N = 404) (N = 407) (N = 811) Age(years) Number 404 407 811 Mean (SD) 57.9 (9.1) 58.5 (9.2) 58.2 (9.2)Median 59.0 59.0 59.0 Min:Max 24:84 27:80 24:84 Age Group (years) [n(%)]Number 404 407 811 <65 317 (78.5%) 304 (74.7%) 621 (76.6%) [65-75[ 80(19.8%) 88 (21.6%) 168 (20.7%) ≥75 7 (1.7%) 15 (3.7%) 22 (2.7%) Gender[n (%)] Number 404 407 811 Male 187 (46.3%) 185 (45.5%) 372 (45.9%)Female 217 (53.7%) 222 (54.5%) 439 (54.1%) Race [n (%)] Number 404 407811 Caucasian/White 378 (93.6%) 383 (94.1%) 761 (93.8%) Black 20 (5.0%)16 (3.9%) 36 (4.4%) Asian/Oriental 3 (0.7%) 7 (1.7%) 10 (1.2%) Other 3(0.7%) 1 (0.2%) 4 (0.5%) Ethnicity [n (%)] Number 404 407 811 Hispanic102 (25.2%) 91 (22.4%) 193 (23.8%) Not Hispanic 302 (74.8%) 316 (77.6%)618 (76.2%) World region [n (%)] Number 404 407 811 North America 175(43.3%) 194 (47.7%) 369 (45.5%) Western Europe 40 (9.9%) 43 (10.6%) 83(10.2%) Eastern Europe 122 (30.2%) 103 (25.3%) 225 (27.7%) Rest of theworld 67 (16.6%) 67 (16.5%) 134 (16.5%) Baseline weight (kg) Number 404407 811 Mean (SD) 98.7 (22.3) 98.0 (20.8) 98.3 (21.6) Median 94.4 95.095.0 Min:Max 48:209 48:188 48:209 Baseline BMI (kg/m²) Number 404 407811 Mean (SD) 34.8 (6.6) 34.8 (6.1) 34.8 (6.4) Median 33.6 34.0 33.8Min:Max 20:63 21:59 20:63 Baseline BMI categories (kg/m²) [n(%)] Number404 407 811 <25 11 (2.7%) 5 (1.2%) 16 (2.0%) [25-30[ 91 (22.5%) 90(22.1%) 181 (22.3%) [30-40[ 215 (53.2%) 244 (60.0%) 459 (56.6%) ≥40 87(21.5%) 68 (16.7%) 155 (19.1%) Baseline estimated GFR (mL/min/1.73 m²)Number 404 407 811 80.47 81.23 Mean (SD) 82.01 (21.73) (20.89) (21.31)Median 81.11 78.69 79.84 Min:Max 22.7:155.3 25.1:158.8 22.7:158.8Baseline estimated GFR categories (mL/min/1.73 m²) [n(%)] Number 404 407811 ≥90 134 (33.2%) 132 (32.4%) 266 (32.8%) [60-90[ 213 (52.7%) 218(53.6%) 431 (53.1%) [30-60[ 55 (13.6%) 55 (13.5%) 110 (13.6%) <30 2(0.5%) 2 (0.5%) 4 (0.5%) Randomization strata of screening HbA1c (%)[n(%)] Number 404 407 811 <8 144 (35.6%) 146 (35.9%) 290 (35.8%) ≥8 260(64.4%) 261 (64.1%) 521 (64.2%) BMI = Body Mass Index GFR = Glomerularfiltration rate GFR is derived from MDRD formula

TABLE 25 Summary of disease characteristics at baseline—Randomizedpopulation HOE901-U300 Lantus All (N = 404) (N = 407) (N = 811) Durationof T2D (years) Number 403 407 810 Mean (SD) 12.7 (7.1) 12.5 (7.0) 12.6(7.0) Median 11.6 11.7 11.7 Min:Max 1:54 1:51 1:54 Category of durationof T2D (years) Number 403 407 810 <10 149 (37.0%) 160 (39.3%) 309(38.1%) ≥10 254 (63.0%) 247 (60.7%) 501 (61.9%) Age at onset of T2D(years) Number 403 407 810 Mean (SD) 45.7 (9.8) 46.5 (9.7) 46.1 (9.7)Median 45.7 46.2 45.9 Min:Max 13:69 18:73 13:73 Duration of basalinsulin treatment (years) Number 404 407 811 Mean (SD) 3.78 (3.73) 3.83(3.34) 3.80 (3.54) Median 2.60 2.70 2.70 Min:Max 0.5:30.6 0.4:24.50.4:30.6 Previous basal insulin type^(a) [n(%)] Number 402 401 803Insulin glargine 301 (74.9%) 332 (82.8%) 633 (78.8%) NPH 101 (25.1%) 69(17.2%) 170 (21.2%) Previous basal insulin daily injection number^(a)[n(%)] Number 402 402 804 Once daily 315 (78.4%) 322 (80.1%) 637 (79.2%)Twice daily 83 (20.6%) 76 (18.9%) 159 (19.8%) More than twice daily 4(1.0%) 4 (1.0%) 8 (1.0%) Previous basal insulin daily closer^(b) (U)Number 378 382 760 65.69 64.89 Mean (SD) 64.08 (25.60) (26.14) (25.87)Median 58.00 56.00 57.55 Q1:Q3 47.00:70.00 47.10:77.30 47.10:74.00Min:Max 32.0:218.6 41.9:200.0 32.0:218.6 Previous basal insulin dailydose^(b) (U/kg) Number 378 382 760 0.681 0.671 Mean (SD) 0.660 (0.221)(0.253) (0.238) Median 0.617 0.609 0.614 Q1:Q3 0.505:0.767 0.504:0.7960.504:0.777 Min:Max 0.31:1.83 0.30:2.02 0.30:2.02 Prior use ofLantus^(c) Number 404 407 811 Yes 304 (75.2%) 337 (82.8%) 641 (79.0%) No100 (24.8%) 70 (17.2%) 170 (21.0%) T2D = Type 2 diabetes ^(a)Previousbasal insulin type and maximal injection number of the patient duringthe last 7 days prior to randomization. ^(b)Mean of the patient from thebasal daily doses during the last 7 days prior to randomization^(c)Taken within 3 months before screening

2.2 Efficacy Evaluation

2.2.1 Primary Efficacy Endpoint

TABLE 26 Main efficacy analysis—Mean change in HbA1c (%) from baselineto Month 6 endpoint using LOCF procedure-mITT population HOE901-U300Lantus HbA1c (%) (N = 403) (N = 405) Baseline Number 386 392 Mean (SD)8.28 (0.87) 8.22 (0.77) Median 8.20 8.10 Min:Max 6.0:12.6 6.7:10.4 Month6 endpoint (LOCF) Number 386 392 Mean (SD) 7.57 (1.02) 7.56 (1.04)Median 7.40 7.50 Min:Max 5.4:14.2 5.3:12.0 Change from baseline to Month6 endpoint (LOCF) Number 386 392 Mean (SD) −0.71 (1.05) −0.66 (0.90)Median −0.70 −0.70 Min:Max −3.9:5.3 −3.4:3.1 LS Mean (SE) ^(a) −0.57(0.094) −0.56 (0.093) 95% Cl (−0.756 to −0.387) (−0.744 to −0.379) LSMean difference −0.01 (0.066) (SE) vs. Lantus ^(a) 95% Cl (−0.139 to0.119) LOCF = Last observation carried forward. ^(a) Analysis ofcovariance (ANCOVA) model with treatment groups (HOE901-U300 andLANTUS), randomization strata of screening HbA1c (<8.0, ≥8.0%) andcountry as fixed effects and baseline HbA1c value as covariate. Note:For all patients rescued during the 6-month period, the lastpostbaseline HbA1c measurement before rescue and during the 6-monthon-treatment period will be used as the HbA1c endpoint.

The data of Table 26 are summarized in FIG. 5.

2.2.2 Main Secondary Endpoints

2.2.2.1 Nocturnal Hypoglycemia

TABLE 27 First main secondary efficacy endpoint-Number (%) of patientswith at least one nocturnal hypoglycemia [00:00 to 05:59] occuringbetween start of Week 9 and Month 6 endpoint (using LOCF procedure),indicated as severe and/or confirmed by plasma glucose ≤3.9 mmol/L (70mg/dL)-mITT population HOE901-U300 Lantus (N = 403) (N = 405) Severeand/or confirmed nocturnal hypoglycemia [00:00 to 05:59] n (%) 87(21.6%) 113 (27.9%) RR (95% Cl) vs. Lantus ^(a) 0.77 (0.61 to 0.99) —p-value (CMH) 0.0380 — n(%) = number and percentage of patients with atleast one nocturnal hypoglycemia event, indicated as severe and/orconfirmed by plasma glucose ≤3.9 mmol/L (70 mg/dL) ^(a) Based on RRstratified by randomization strata of screening HbA1c (<8.0 or ≥8.0%),using a CMH methodology

2.2.2.2 Pre-Injection Plasma Glucose—Month 6 Endpoint

TABLE 28 Second main secondary efficacy endpoint—Mean change in averagepre-injection SMPG (mmol/L) from baseline to Month 6 endpoint using LOCFprocedure-mITT population Average pre-injection HOE901-U300 Lantus SMPG(mmol/L) (N = 403) (N = 405) Baseline Number 353 350 Mean (SD) 11.01(2.92) 10.84 (2.79) Median 10.55 10.48 Min:Max 5.0:21.8 4.8:18.8 Month 6endpoint (LOCF) Number 353 350 Mean (SD) 10.23 (3.03) 10.28 (3.05)Median 9.77 9.52 Min:Max 5.1:25.1 5.1:20.4 Change from baseline to Month6 endpoint (LOCF) Number 353 350 Mean (SD) −0.78 (3.10) −0.57 (3.01)Median −0.82 −0.72 Min:Max −9.6:9.9 −8.8:10.9 LS Mean (SE) ^(b) −0.56(0.278) −0.51 (0.275) 95% Cl (−1.101 to −0.010) (−1.052 to 0.028) LSMean difference −0.04 (0.201) (SE) vs. Lantus ^(b) 95% Cl (−0.438 to0.350) p-value(ANCOVA) 0.8279 LOCF = Last observation carried forward.SMPG = Self Monitoring Plasma Glucose ^(a) Average is assessed by themean of at least 3 SMPG calculated over the 7 days preceding the givenvisit. ^(b) Analysis of covariance (ANCOVA) model with treatment groups(HOE901-U300 and LANTUS), randomization strata of screening HbA1c (<8.0,≥8.0%) and country as fixed effects and baseline average pre-injectionSMPG value as covariate. Note: For all patients rescued during the6-month period, the last postbaseline average pre-injection SMPGmeasurement before rescue and during the 6-month on-treatment periodwill be used as the average pre-injection SMPG endpoint.

The data of Table 28 are summarized in FIG. 6.

2.2.2.3 Variability of Preinjection SMPG—Month 6 Endpoint

TABLE 29 Third main secondary efficacy endpoint—Mean change invariability of pre-injection SMPG from baseline to Month 6 endpointusing LOCF procedure-mITT population HOE901-U300 Lantus Variability ofpre-injection SMPG (N = 403) (N = 405) Baseline Number 353 350 Mean (SD)22.44 (11.73) 20.89 (10.46) Median 21.77 20.04 Min:Max 0.0:86.6 0.0:57.0Month 6 endpoint (LOCF) Number 353 350 Mean (SD) 19.84 (10.40) 20.37(11.65) Median 18.95 18.89 Min:Max 2.3:58.0 1.2:73.5 Change frombaseline to Month 6 endpoint (LOCF) Number 353 350 Mean (SD) −2.60(14.00) −0.52 (13.32) Median −1.69 −0.54 Min:Max −66.6:46.4 −37.8:67.1LS Mean (SE) ^(a) −2.34 (1.425) −0.53 (1.408) 95% Cl (−5.142 to 0.452)(−3.297 to 2.231) LS Mean difference −1.81 (1.029) (SE) vs. Lantus ^(a)95% Cl (−3.833 to 0.210) LOCF = Last observation carried forward. SMPG =Self Monitoring Plasma Glucose Variability is assessed by the mean ofcoefficient of variation calculated over at least 3 SMPG measured duringthe 7 days preceding the given visit ^(a) Analysis of variance (ANOVA)model with treatment groups (HOE901-U300 and LANTUS), randomizationstrata of screening HbA1c (<8.0, ≥8.0%) and country as fixed effectsNote: For all patients rescued during the 6-month period, the lastpostbaseline variability of pre-injection SMPG measurement before rescueand during the 6-month on-treatment period will be used as thevariability of pre-injection SMPG endpoint.

2.2.3 Other Secondary Efficacy Endpoints

2.2.3.1 Percentage of Patients with HbA1c<7% at Month 6

TABLE 30 Other secondary efficacy endpoint—Number (%) of patients withHbA1c <7% at Month 6 endpoint (using LOCF procedure) and Number (%) ofpatients with HbA1c <7% at Month 6 endpoint (using LOCF procedure)having experienced no hypoglycemia indicated as severe and/or confirmedby plasma glucose <3 mmol/L (54 mg/dL) during the last 3 months of themain 6-month treatment period-mITT population HOE901-U300 Lantus (N =403) (N = 405) HbA1c <7% Number 386 392 n (%) 118 (30.6%) 119 (30.4%) RR(95% Cl) vs. Lantus ^(a) 1.02 (0.83 to 1.25) — HbA1c <7% and no emergentsevere or confirmed (<3.0 mmol/L; <54 mg/dL) hypoglycemia Number 387 396n (%) 93 (24.0%) 94 (23.7%) RR (95% Cl) vs. Lantus ^(a) 1.02 (0.80 to1.31) — HbA1c <7% and no nocturnal [00:00-05:59] emergent severe orconfirmed (<3.0 mmol/L; <54 mg/dL) hypoglycemia Number 386 394 n (%) 107(27.7%) 113 (28.7%) RR (95% Cl) vs. Lantus ^(a) 0.98 (0.78 to 1.22) —LOCF = Last observation carried forward. RR = relative risk ^(a) Basedon RR stratified by randomization strata of screening HbA1c (<8.0 or≥8.0 %), using a CMH methodology Note: For all patients rescued duringthe 6-month period, the last postbaseline HbA1c measurement beforerescue and during the 6-month on-treatment period will be used as theHbA1c endpoint.

2.2.3.2 Change in FPG from Baseline to Month 6 Endpoint

TABLE 31 Other secondary efficacy endpoint—Mean change in FPG (mmol/L)from baseline to Month 6 endpoint using LOCF procedure-mITT populationHOE901-U300 Lantus FPG (mmol/L) (N = 403) (N = 405) Baseline Number 375379 Mean (SD) 8.24 (2.97) 7.89 (2.67) Median 7.80 7.40 Min:Max 2.7:20.12.9:16.6 Month 6 endpoint (LOCF) Number 375 379 Mean (SD) 7.09 (2.47)6.83 (2.37) Median 6.70 6.30 Min:Max 2.9:24.4 2.8:17.9 Change frombaseline to Month 6 endpoint (LOCF) Number 375 379 Mean (SD) −1.14(3.42) −1.06 (3.02) Median −0.90 −0.90 Min:Max −13.1:11.0 −11.2:10.5 LSMean (SE) ^(a) −1.03 (0.242) −1.21 (0.241) 95% Cl (−1.501 to −0.551)(−1.687 to −0.741) LS Mean difference 0.19 (0.171) (SE) vs. Lantus ^(a)95% Cl (−0.148 to 0.524) FPG = Fasting Plasma Glucose LOCF = Lastobservation carried forward. ^(a) Analysis of covariance (ANCOVA) modelwith treatment groups (HOE901-U300 and LANTUS), randomization strata ofscreening HbA1c (<8.0, ≥8.0%) and country as fixed effects and baselineFPG value as covariate. Note: For all patients rescued during the6-month period, the last postbaseline FPG measurement before rescue andduring the 6-month on-treatment period will be used as the FPG endpoint.

2.2.3.3 Eight-Point SMPG Profile

The mean 8-point SMPG profile (mmol/l) at baseline and Month 6 endpoint(mITT population) is described in FIG. 7.

2.2.3.4 Basal Insulin Dose

The average daily basal insulin dose (U) by visit during the main6-month on-treatment period (mITT population) is described in FIG. 8.

2.3 Safety Evaluation

2.3.1 Extent of Exposure

TABLE 32 Exposure to investigational product for the main 6-monthon-treatment period—Safety population HOE901-U300 Lantus (N = 403) (N =406) Cumulative exposure to 191.1 193.6 main 6-month treatment (patientyears) Duration of main 6-month study treatment (days) Number 402 406Mean (SD) 1737 (357) 174.2 (33.0) Median 183.0 183.0 Min:Max 1:208 4:228Duration of main 6-month study treatment by category [n(%)]   up to 2weeks 6 (1.5%) 2 (0.5%)   >2 to 4 weeks 4 (1.0%) 6 (1.5%)   >4 to 8weeks 7 (1.7%) 6 (1.5%)  >8 to 12 weeks 6 (1.5%) 7 (1.7%) >12 to 17weeks 2 (0.5%) 5 (1.2%) >17 to 26 weeks 117 (29.1%) 110 (27.1%) >26weeks 260 (64.7%) 270 (66.5%) Cumulative duration of main 6-month studytreatment by category [n(%)]  ≥1 days 402 (100%) 406 (100%)  >2 weeks396 (98.5%) 404 (99.5%)  >4 weeks 392 (97.5%) 398 (98.0%)  >8 weeks 385(95.8%) 392 (96.6%) >12 weeks 379 (94.3%) 385 (94.8%) >17 weeks 377(93.8%) 380 (93.6%) >26 weeks 260 (64.7%) 270 (66.5%) Note: Patients areconsidered in the treatment group they actually received atrandomization

2.3.2 Hypoglycemia

TABLE 33 Number (%) of patients with at least one emergent hypoglycemiaevent during the main 6-month on-treatment period—Safety population AllNocturnal hypoglycemia hypoglycemia (00:00-05:59) Type of hypoglycemiaHOE901-U300 Lantus HOE901-U300 Lantus event n(%) (N = 403) (N = 406) (N= 403) (N = 406) Any hypoglycemia event 288 (71.5%) 322 (79.3%) 123(30.5%) 169 (41.6%) Severe hypoglycemia 4 (1.0%) 6 (1.5%) 0 2 (0.5%)Documented symptomatic hypoglycemia ≤3.9 mmol/L (70 mg/dL) 200 (49.6%)233 (57.4%) 91 (22.6%) 126 (31.0%) <3.0 mmol/L (54 mg/dL) 83 (20.6%) 109(26.8%) 33 (8.2%) 47 (11.6%) Asymptomatic hypoglycemia ≤3.9 mmol/L (70mg/dL) 200 (49.6%) 238 (58.6%) 43 (10.7%) 77 (19.0%) <3.0 mmol/L (54mg/dL) 43 (10.7%) 59 (14.5%) 10 (2.5%) 9 (2.2%) Probable symptomatic 6(1.5%) 10 (2.5%) 3 (0.7%) 3 (0.7%) hypoglycemia Relativehypoglycemia >3.9 mmol/L (70 mg/dL) 23 (5.7%) 45 (11.1%) 9 (2.2%) 23(5.7%) Nocturnal hypoglycemia Severe and/or confirmed^(a) hypoglycemia≤3.9 mmol/L (70 mg/dL) 282 (70.0%) 314 (77.3%) 114 (28.3%) 162 (39.9%)<3.0 mmol/L (54 mg/dL) 110 (27.3%) 143 (35.2%) 40 (9.9%) 54 (13.3%) n(%) = number and percentage of patients with at least one hypoglycemiaevent ^(a)Severe and/or confirmed hypoglycemia = severe and/or confirmedby plasma glucose ≤3.9 mmol/L (70 mg/dL) (resp. ≤3.0 mmol/L (54 mg/dL))

TABLE 34 Number (%) of patients with at least one emergent hypoglycemiaevent during the main 6-month on-treatment period by study period—Safetypopulation Nocturnal hypoglycemia All hypoglycemia (00:00-05:59) Type ofhypoglycemia event HOE901-U300 Lantus HOE901-U300 Lantus n(%) (N = 403)(N = 406) (N = 403) (N = 406) Any hypoglycemia event Overall 288 (71.5%)322 (79.3%) 123 (30.5%) 169 (41.6%) Treatment Start to Week 8 198(49.1%) 258 (63.5%) 58 (14.4%) 109 (26.8%) From start of week 9 to 241(59.8%) 267 (65.8%) 94 (23.3%) 119 (29.3%) Month 6 Severe hypoglycemiaOverall 4 (1.0%) 6 (1.5%) 0 2 (0.5%) Treatment Start to Week 8 1 (0.2%)2 (0.5%) 0 0 From start of week 9 3 (0.7%) 5 (1.2%) 0 2 (0.5%) to Month6 Documented symptomatic hypoglycemia ≤3.9 mmol/L (70 mg/dL) 200 (49.6%)233 (57.4%) 91 (22.6%) 126 (31.0%) Overall Treatment Start to 119(29.5%) 158 (38.9%) 34 (8.4%) 79 (19.5%) Week 8 From start of week 9 to163 (40.4%) 180 (44.3%) 77 (19.1%) 90 (22.2%) Month 6 <3.0 mmol/L (54mmg/dL) 83 (20.6%) 109 (26.8%) 33 (8.2%) 47 (11.6%) Overall TreatmentStart to 35 (8.7%) 55 (13.5%) 10 (2.5%) 26 (6.4%) Week 8 From start ofweek 9 to 64 (15.9%) 81 (20.0%) 27 (6.7%) 35 (8.6%) Month 6 Asymptomatichypoglycemia ≤3.9 mmol/L (70 mg/dL) 200 (49.6%) 238 (58.6%) 43 (10.7%)77 (19.0%) Overall Treatment Start to Week 131 (32.5%) 171 (42.1%) 22(5.5%) 46 (11.3%) 8 From start of week 9 to 163 (40.4%) 195 (48.0%) 25(6.2%) 50 (12.3%) Month 6 <3.0 mmol/L (54 mg/dL) 43 (10.7%) 59 (14.5%)10 (2.5%) 9 (2.2%) Overall Treatment Start to Week 22 (5.5%) 30 (7.4%) 7(1.7%) 5 (1.2%) 8 From start of week 9 to 26 (6.5%) 40 (9.9%) 4 (1.0%) 5(1.2%) Month 6 Severe and/or confirmed^(a) hypoglycemia ≤3.9 mmol/L (70mg/dL) 282 (70.0%) 314 (77.3%) 114 (28.3%) 162 (39.9%) Overall TreatmentStart to Week 190 (47.1%) 244 (60.1%) 53 (13.2%) 100 (24.6%) 8 Fromstart of week 9 to 239 (59.3%) 264 (65.0%) 89 (22.1%) 117 (28.8%) Month6 <3.0 mmol/L (54 mg/dL) 110 (27.3%) 143 (35.2%) 40 (9.9%) 54 (13.3%)Overall Treatment Start to Week 52 (12.9%) 79 (19.5%) 16 (4.0%) 29(7.1%) 8 From start of week 9 to 82 (20.3%) 107 (26.4%) 29 (7.2%) 39(9.6%) Month 6 n (%) = number and percentage of patients with at leastone hypoglycemia event ^(a)Severe and/or confirmed hypoglycemia = severeand/or confirmed by plasma glucose ≤3.9 mmol/L (70 mg/dL) (resp. ≤3.0mmol/L (54 mg/dL))

2.3.3 Treatment-Emergent Adverse Events

TABLE 35 Treatment emergent adverse events during the main 6-monthon-treatment period-Safety population HOE901-U300 Lantus n (%) (N = 403)(N = 406) Patients with any TEAE 236 (58.6%) 206 (50.7%) Patients withany treatment emergent SAE 15 (3.7%) 15 (3.7%) Patients with any TEAEleading to death 2 (0.5%) 1 (0.2%) Patients with any TEAE 6 (1.5%) 4(1.0%) leading to permanent treatment discontinuation TEAE: Treatmentemergent adverse event, SAE:Serious Adverse Event n (%) = number andpercentage of patients with at least one TEAE

TABLE 36 Number (%) of patients with TEAE(s) that occurred with HLT ≥ 2%in any treatment group by Primary SOC, HLT and PT for the main 6-monthon-treatment period—Safety population PRIMARY SYSTEM ORGAN CLASS HLT:High Level Term HOE901-U300 Lantus Preferred Term n (%) (N = 403) (N =406) Any class 236 (58.6%) 206 (50.7%) INFECTIONS AND INFESTATIONS 133(33.0%) 129 (31.8%) HLT: Influenza viral infections 11 (2.7%) 11 (2.7%)Influenza 11 (2.7%) 11 (2.7%) HLT: Lower respiratory tract and lunginfections 20 (5.0%) 18 (4.4%) Bronchitis 19 (4.7%) 14 (3.4%) Lowerrespiratory tract infection 0  1 (0.2%) Pneumonia  1 (0.2%)  3 (0.7%)HLT: Upper respiratory tract infections  72 (17.9%)  72 (17.7%) Acutesinusitis  2 (0.5%)  2 (0.5%) Acute tonsillitis  1 (0.2%) 0 Chronicsinusitis  1 (0.2%) 0 Laryngitis  1 (0.2%) 0 Nasopharyngitis 39 (9.7%)27 (6.7%) Pharyngitis  4 (1.0%) 10 (2.5%) Pharyngotonsillitis 0  2(0.5%) Sinusitis  7 (1.7%)  9 (2.2%) Tonsillitis  2 (0.5%) 0 Tracheitis 1 (0.2%) 0 Upper respiratory tract infection 17 (4.2%) 28 (6.9%) HLT:Urinary tract infections 13 (3.2%) 11 (2.7%) Pyelonephritis acute  1(0.2%) 0 Pyelonephritis chronic 0  1 (0.2%) Urinary tract infection 12(3.0%) 10 (2.5%) HLT: Viral infections NEC 13 (3.2%) 10 (2.5%)Conjunctivitis viral  1 (0.2%) 0 Gastroenteritis viral  5 (1.2%)  3(0.7%) Gastrointestinal viral infection 0  1 (0.2%) Respiratory tractinfection viral 0  3 (0.7%) Viral infection  1 (0.2%) 0 Viralpharyngitis  1 (0.2%) 0 Viral upper respiratory tract infection  5(1.2%)  3 (0.7%) NERVOUS SYSTEM DISORDERS  47 (11.7%) 38 (9.4%) HLT:Headaches NEC 20 (5.0%) 16 (3.9%) Headache 19 (4.7%) 16 (3.9%) Sinusheadache  1 (0.2%) 0 Tension headache  1 (0.2%) 0 VASCULAR DISORDERS 14(3.5%) 15 (3.7%) HLT: Vascular hypertensive disorders NEC 11 (2.7%)  6(1.5%) Hypertension 11 (2.7%)  6 (1.5%) GASTROINTESTINAL DISORDERS  44(10.9%) 34 (8.4%) HLT: Diarrhoea (excl infective) 15 (3.7%)  9 (2.2%)Diarrhoea 15 (3.7%)  9 (2.2%) HLT: Nausea and vomiting symptoms 14(3.5%)  9 (2.2%) Nausea  9 (2.2%)  4 (1.0%) Vomiting  5 (1.2%)  5 (1.2%)MUSCULOSKELETAL AND CONNECTIVE  44 (10.9%)  41 (10.1%) TISSUE DISORDERSHLT: Musculoskeletal and connective tissue pain 20 (5.0%) 22 (5.4%) anddiscomfort Back pain  9 (2.2%) 12 (3.0%) Flank pain  1 (0.2%) 0Musculoskeletal chest pain 0  1 (0.2%) Musculoskeletal discomfort 0  1(0.2%) Musculoskeletal pain  4 (1.0%)  2 (0.5%) Neck pain  3 (0.7%)  3(0.7%) Pain in extremity  5 (1.2%)  3 (0.7%) GENERAL DISORDERS ANDADMINISTRATION 28 (6.9%) 29 (7.1%) SITE CONDITIONS HLT: Injection sitereactions  4 (1.0%) 12 (3.0%) Injection site atrophy 0  1 (0.2%)Injection site bruising 0  2 (0.5%) Injection site erythema 0  2 (0.5%)Injection site haemorrhage  2 (0.5%)  5 (1.2%) Injection site induration0  3 (0.7%) Injection site inflammation  1 (0.2%) 0 Injection siteirritation 0  1 (0.2%) Injection site pain  1 (0.2%)  4 (1.0%) Injectionsite reaction  1 (0.2%)  1 (0.2%) Injection site swelling 0  1 (0.2%)HLT: Oedema NEC  6 (1.5%) 12 (3.0%) Oedema peripheral  6 (1.5%) 12(3.0%) INJURY, POISONING AND PROCEDURAL 34 (8.4%) 21 (5.2%)COMPLICATIONS HLT: Muscle, tendon and ligament injuries 11 (2.7%)  3(0.7%) Epicondylitis 0  1 (0.2%) Ligament rupture  1 (0.2%) 0 Ligamentsprain  7 (1.7%) 0 Muscle strain  2 (0.5%)  1 (0.2%) Post-traumatic necksyndrome  1 (0.2%)  1 (0.2%) TEAE: Treatment emergent adverse event,SOC: System organ class, HLT: High level term, PT: Preferred term MedDRA16.0 n (%) = number and percentage of patients with at least one TEAENote: Table sorted by SOC internationally agreed order and HLT, PT byalphabetic order Only HLT with at least one HLT ≥ 2% in at least onegroup are presented

2.3.4 Deaths, Serious Treatment-Emergent Adverse Events

2.3.4.1 Death

TABLE 37 Number (%) of patients who died by study period (on study,on-treatment, post-study)—Safety population HOE901-U300 Lantus (N = 403)(N = 406) Death on-study^(a) 3 (0.7%) 2 (0.5%) Death on-study duringfirst 6 months 2 (0.5%) 1 (0.2%) Death on-treatment^(b) 2 (0.5%) 1(0.2%) Death post-study^(c) 0 0 TEAE: Treatment emergent adverse event,SAE: Serious adverse event ^(a)Includes all deaths that occurred afterthe start of treatment up to end of study (defined as last protocolplanned visit or the resolution/stabilization of all treatment emergentSAE and adverse event of pre-specified monitoring) ^(b)On-treatment ismain 6-month on-treatment period ^(c)Includes deaths that occurred afterthe end of the study (as defined in footnote a) and reported in thedatabase

2.3.4.2 Serious Adverse Events

TABLE 38 Number (%) of patients with treatment emergent SAEs by PrimarySOC, HLGT, HLT and PT for the main 6-month on-treatment period—Safetypopulation PRIMARY SYSTEM ORGAN CLASS HLGT: High Level Group Term HLT:High Level Term HOE901-U300 Lantus Preferred Term n (%) (N = 403) (N =406) Any class 15 (3.7%)  15 (3.7%)  INFECTIONS AND INFESTATIONS 2(0.5%) 7 (1.7%) HLGT: Infections-pathogen unspecified 2 (0.5%) 7 (1.7%)HLT: Infections NEC 1 (0.2%) 2 (0.5%) Infected bites 0 1 (0.2%)Localised infection 0 1 (0.2%) Wound infection 1 (0.2%) 0 HLT: Lowerrespiratory tract and lung 0 1 (0.2%) infections Pneumonia 0 1 (0.2%)HLT: Upper respiratory tract infections 1 (0.2%) 1 (0.2%) Chronicsinusitis 1 (0.2%) 0 Upper respiratory tract infection 0 1 (0.2%) HLT:Urinary tract infections 0 3 (0.7%) Pyelonephritis chronic 0 1 (0.2%)Urinary tract infection 0 2 (0.5%) NEOPLASMS BENIGN, MALIGNANT AND 1(0.2%) 1 (0.2%) UNSPECIFIED (INCL CYSTS AND POLYPS) HLGT: Leukaemias 1(0.2%) 0 HLT: Myelodysplastic syndromes 1 (0.2%) 0 Myelodysplasticsyndrome 1 (0.2%) 0 HLGT: Skin neoplasms malignant and 0 1 (0.2%)unspecified HLT: Skin melanomas (excl ocular) 0 1 (0.2%) Malignantmelanoma 0 1 (0.2%) METABOLISM AND NUTRITION DISORDERS 0 1 (0.2%) HLGT:Glucose metabolism disorders (incl 0 1 (0.2%) diabetes mellitus) HLT:Hypoglycaemic conditions NEC 0 1 (0.2%) Hypoglycaemia 0 1 (0.2%) NERVOUSSYSTEM DISORDERS 1 (0.2%) 3 (0.7%) HLGT: Central nervous system vascular0 2 (0.5%) disorders HLT: Central nervous system haemorrhages 0 2 (0.5%)and cerebrovascular accidents Ischaemic stroke 0 2 (0.5%) HLGT:Neurological disorders NEC 1 (0.2%) 1 (0.2%) HLT: Neurological signs andsymptoms NEC 1 (0.2%) 0 Cerebrospinal fluid leakage 1 (0.2%) 0 HLT:Sensory abnormalities NEC 0 1 (0.2%) Hypoaesthesia 0 1 (0.2%) CARDIACDISORDERS 6 (1.5%) 1 (0.2%) HLGT: Cardiac arrhythmias 0 1 (0.2%) HLT:Rate and rhythm disorders NEC 0 1 (0.2%) Nodal rhythm 0 1 (0.2%) HLGT:Cardiac disorder signs and symptoms 2 (0.5%) 0 HLT: Cardiac disordersNEC 2 (0.5%) 0 Cardiac disorder 1 (0.2%) 0 Cardiovascular disorder 1(0.2%) 0 HLGT: Coronary artery disorders 2 (0.5%) 0 HLT: Ischaemiccoronary artery disorders 2 (0.5%) 0 Acute myocardial infarction 1(0.2%) 0 Myocardial infarction 1 (0.2%) 0 HLGT: Heart failures 2 (0.5%)0 HLT: Heart failures NEC 2 (0.5%) 0 Cardiac failure 1 (0.2%) 0 Cardiacfailure congestive 1 (0.2%) 0 VASCULAR DISORDERS 0 1 (0.2%) HLGT:Decreased and nonspecific blood 0 1 (0.2%) pressure disorders and shockHLT: Vascular hypotensive disorders 0 1 (0.2%) Hypotension 0 1 (0.2%)RESPIRATORY, THORACIC AND MEDIASTINAL 1 (0.2%) 0 DISORDERS HLGT:Bronchial disorders (excl neoplasms) 1 (0.2%) 0 HLT: Bronchospasm andobstruction 1 (0.2%) 0 Asthma 1 (0.2%) 0 GASTROINTESTINAL DISORDERS 1(0.2%) 0 HLGT: Gastrointestinal haemorrhages NEC 1 (0.2%) 0 HLT:Non-site specific gastrointestinal 1 (0.2%) 0 haemorrhages Lowergastrointestinal haemorrhage 1 (0.2%) 0 SKIN AND SUBCUTANEOUS TISSUE 1(0.2%) 1 (0.2%) DISORDERS HLGT: Angioedema and urticaria 1 (0.2%) 0 HLT:Urticarias 1 (0.2%) 0 Urticaria 1 (0.2%) 0 HLGT: Skin and subcutaneoustissue disorders 0 1 (0.2%) NEC HLT: Skin and subcutaneous tissue 0 1(0.2%) ulcerations Skin ulcer 0 1 (0.2%) MUSCULOSKELETAL AND CONNECTIVE0 1 (0.2%) TISSUE DISORDERS HLGT: Joint disorders 0 1 (0.2%) HLT:Osteoarthropathies 0 1 (0.2%) Osteoarthritis 0 1 (0.2%) RENAL ANDURINARY DISORDERS 0 1 (0.2%) HLGT: Urolithiases 0 1 (0.2%) HLT: Urinarytract lithiasis (excl renal) 0 1 (0.2%) Calculus urinary 0 1 (0.2%)GENERAL DISORDERS AND ADMINISTRATION 1 (0.2%) 0 SITE CONDITIONS HLGT:Fatal outcomes 1 (0.2%) 0 HLT: Death and sudden death 1 (0.2%) 0 Suddencardiac death 1 (0.2%) 0 INJURY, POISONING AND PROCEDURAL 1 (0.2%) 0COMPLICATIONS HLGT: Injuries NEC 1 (0.2%) 0 HLT: Skin injuries NEC 1(0.2%) 0 Contusion 1 (0.2%) 0 SAE: Serious adverse event, SOC: Systemorgan class, HLGT: High level group term, HLT: High level term, PT:Preferred term MedDRA 16.0 n (%) = number and percentage of patientswith at least one treatment emergent SAE Note: Table sorted by SOCinternationally agreed order and HLGT, HLT, PT by alphabetic order

2.3.5 Adverse Events Leading to Withdrawal

TABLE 39 Number (%) of patients with TEAE(s) leading to permanenttreatment discontinuation by Primary SOC, HLGT, HLT and PT for the main6-month on-treatment period—Safety population PRIMARY SYSTEM ORGAN CLASSHLGT: High Level Group Term HLT: High Level Term HOE901-U300 LantusPreferred Term n (%) (N = 403) (N = 406) Any class 6 (1.5%) 4 (1.0%)INFECTIONS AND INFESTATIONS 0 1 (0.2%) HLGT: Infections-pathogenunspecified 0 1 (0.2%) HLT: Urinary tract infections 0 1 (0.2%)Pyelonephritis chronic 0 1 (0.2%) NEOPLASMS BENIGN, MALIGNANT AND 1(0.2%) 0 UNSPECIFIED (INCL CYSTS AND POLYPS) HLGT: Leukaemias 1 (0.2%) 0HLT: Myelodysplastic syndromes 1 (0.2%) 0 Myelodysplastic syndrome 1(0.2%) 0 BLOOD AND LYMPHATIC SYSTEM DISORDERS 1 (0.2%) 0 HLGT: Whiteblood cell disorders 1 (0.2%) 0 HLT: Neutropenias 1 (0.2%) 0 Neutropenia1 (0.2%) 0 METABOLISM AND NUTRITION DISORDERS 0 1 (0.2%) HLGT: Glucosemetabolism disorders (incl 0 1 (0.2%) diabetes mellitus) HLT:Hypoglycaemic conditions NEC 0 1 (0.2%) Hypoglycaemia 0 1 (0.2%)PSYCHIATRIC DISORDERS 0 2 (0.5%) HLGT: Manic and bipolar mood disordersand 0 1 (0.2%) disturbances HLT: Bipolar disorders 0 1 (0.2%) Bipolardisorder 0 1 (0.2%) HLGT: Sleep disorders and disturbances 0 1 (0.2%)HLT: Disturbances in initiating and 0 1 (0.2%) maintaining sleepInsomnia 0 1 (0.2%) NERVOUS SYSTEM DISORDERS 1 (0.2%) 0 HLGT: Cranialnerve disorders (excl neoplasms) 1 (0.2%) 0 HLT: Eye movement disorders1 (0.2%) 0 IIIrd nerve paralysis 1 (0.2%) 0 CARDIAC DISORDERS 1 (0.2%) 0HLGT: Coronary artery disorders 1 (0.2%) 0 HLT: Ischaemic coronaryartery disorders 1 (0.2%) 0 Myocardial infarction 1 (0.2%) 0 RENAL ANDURINARY DISORDERS 1 (0.2%) 0 HLGT: Nephropathies 1 (0.2%) 0 HLT:Nephropathies and tubular disorders 1 (0.2%) 0 NEC Diabetic nephropathy1 (0.2%) 0 GENERAL DISORDERS AND ADMINISTRATION 1 (0.2%) 0 SITECONDITIONS HLGT: Fatal outcomes 1 (0.2%) 0 HLT: Death and sudden death 1(0.2%) 0 Sudden cardiac death 1 (0.2%) 0 TEAE: Treatment emergentadverse event, SOC: System organ class, HLGT: High level group term,HLT: High level term, PT: Preferred term MedDRA 16.0 n (%) = number andpercentage of patients with at least one TEAE leading to permanenttreatment discontinuation Note: Table sorted by SOC internationallyagreed order and HLGT, HLT, PT by alphabetic order

2.3.6 Other Significant Adverse Events

2.3.6.1 Hypersensitivity Reaction

TABLE 40 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term—Hypersensitivityreactions during the main 6-month on-treatment period—Safety populationHOE901-U300 Lantus Preferred Term (N = 403) (N = 406) Anyhypersensitivity reactions 13 (3.2%)  16 (3.9%)  Asthma 2 (0.5%) 3(0.7%) Allergic cough 1 (0.2%) 0 Allergy to chemicals 1 (0.2%) 0Bronchial hyperreactivity 1 (0.2%) 0 Dermatitis infected 1 (0.2%) 0 Drughypersensitivity 1 (0.2%) 1 (0.2%) Eczema 1 (0.2%) 0 Rash 1 (0.2%) 3(0.7%) Rhinitis allergic 1 (0.2%) 2 (0.5%) Seasonal allergy 1 (0.2%) 1(0.2%) Sneezing 1 (0.2%) 0 Urticaria 1 (0.2%) 0 Asthmatic crisis 0 1(0.2%) Blister 0 1 (0.2%) Erythema 0 3 (0.7%) Neurodermatitis 0 1 (0.2%)MedDRA 16.0 TEAE: Treatment emergent adverse event n (%) = number andpercentage of patients with at least one hypersensitivity reaction event

2.3.6.2 Injection Site Reactions

TABLE 41 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term—Injection sitereactions during the main 6-month on-treatment period—Safety populationHOE901-U300 Lantus Preferred Term (N = 403) (N = 406) Any injection sitereaction 4 (1.0%) 12 (3.0%)  Injection site haemorrhage 2 (0.5%) 5(1.2%) Injection site inflammation 1 (0.2%) 0 Injection site pain 1(0.2%) 4 (1.0%) Injection site reaction 1 (0.2%) 1 (0.2%) Injection siteatrophy 0 1 (0.2%) Injection site bruising 0 2 (0.5%) Injection siteerythema 0 2 (0.5%) Injection site induration 0 3 (0.7%) Injection siteirritation 0 1 (0.2%) Injection site swelling 0 1 (0.2%) MedDRA 16.0TEAE: Treatment emergent adverse event n (%) = number and percentage ofpatients with at least one local tolerability at injection site event

2.3.7 Body Weight

TABLE 42 Vital signs—Descriptive statistics—Mean change in Weight (kg)from baseline to Month 6 endpoint using LOCF procedure during the main6-month on-treatment period—Safety population HOE901-U300 Lantus Weight(kg) (N = 403) (N = 406) Baseline Number 400   403   Mean (SD) 98.78(22.37) 98.17 (20.73) Median  94.50  95.10 Min:Max 48.0:208.6 55.0:187.7Month 6 endpoint (LOCF) Number 400   403   Mean (SD) 98.86 (22.09) 98.84(20.63) Median  94.70  96.00 Min:Max 46.5:213.2 57.9:189.1 Change frombaseline to Month 6 endpoint (LOCF) Number 400   403   Mean (SD) 0.08(3.44) 0.66 (3.01) Median   0.00   0.64 Min:Max −22.1:12.4  −23.3:9.9    LOCF = Last observation carried forward.

EXAMPLE 3: 6-MONTH, MULTICENTER, RANDOMIZED, OPEN-LABEL, PARALLEL-GROUPSTUDY COMPARING THE EFFICACY AND SAFETY OF A NEW FORMULATION OF INSULINGLARGINE AND LANTUS® BOTH PLUS MEALTIME INSULIN IN PATIENTS WITH TYPE 2DIABETES MELLITUS WITH A 6-MONTH SAFETY EXTENSION PERIOD—ADMINISTRATIONSUB-STUDY COMPARING ADAPTABLE DOSING INTERVALS WITH FIXED DOSINGINTERVALS

1 Synopsis

Phase of development:

3

Objectives:

Primary Objective: To compare the efficacy of HOE901-U300 injected oncedaily every 24 hours and HOE901-U300 injected once daily at intervals of24±3 hours in terms of change of HbA1c from month 6 of the main study(=baseline of sub-study) to month 9 of the main study (=endpoint ofsub-study) in patients with type 2 diabetes mellitus.

Main secondary Objectives: To compare the safety of the two injectionregimens for HOE901-U300 in terms of occurrence of hypoglycemia.

Methodology:

Patients randomized on HOE901-U300 and having received HOE901-U300 inthe 6-month main study period are randomized 1:1 to administerHOE901-U300 once daily either every 24 hours (fixed dosing intervals) orevery 24±3 hours (adaptable dosing intervals).

Patients on HOE901-U300 completing the 6 months main study period (seeExample 1) and meeting the eligibility criteria for the sub-study wereeligible for the sub-study. No specific sample size was requested forthe primary analysis that is descriptive.

Number of patients: Planned: up to 300 (150 pre-treatment arm)Randomized: 110 Treated: 110 Evaluated: Efficacy: 109 Safety: 110

Diagnosis and Criteria for Inclusion:

Inclusion criteria: Completion of the 6-month study period in main studydescribed in Example 1 (Visit 10), Randomized and treated withHOE901-U300 during the 6-month treatment period (Baseline—month 6),Signed written informed consent for sub-study obtained.

Key Exclusion Criteria:

Patient not willing to use the adaptable injection intervals of 24±3hours on at least two days per week; In the investigator's opinion, notable to comply with an adaptable dosing schedule; Health condition whichprecludes further participation of the patient in the study.

Study Treatments

Investigational Medicinal Product:

Tested drug: HOE901-U300

Formulation: HOE901-U300 (insulin glargine 300 U/mL solution) is asterile, non-pyrogenic, clear, colorless solution in a glass cartridgeassembled in a pen-injector (prefilled, disposable pen).

Route of administration: subcutaneous injection

Tested Regimen:

Adaptable dosing intervals: HOE901-U300 administered once daily every24±3 hours.

The injection time may have been adapted according to individual needsby up to 3 hours earlier or later than the daily injection time in theevening fixed at the start of the main study. The maximum intervals, ie,3 hours earlier or 3 hours later than the fixed daily injection time wasto be used on at least 2 days of the week at the patients' choice. Theinjection time fixed at start of the main study was to be maintained asreference time for the variation.

Control Regimen:

Fixed dosing intervals: HOE901-U300, once daily injection every 24hours.

Patients continued to inject HOE901-U300 once daily every 24 hours atthe injection time fixed at start of the main study.

Dose:

The dose of HOE901-U300 was to be titrated as needed to achieve ormaintain fasting plasma glucose in the target range of 80 to 100 mg/dL(4.4 mmol/L to 5.6 mmol/L) without hypoglycemia. Changes in the insulindose were based on fasting self-monitored capillary plasma glucose(SMPG) measurements.

Non-Investigational Medicinal Products

Patients in both treatment groups were to continue with their mealtimeinsulin analogue during the sub-study.

Patients on concomitant metformin treatment were to continue during thesub-study on a stable dose, unless safety concerns necessitated a dosereduction or discontinuation of metformin

Duration of Treatment:

The sub-study consisted of a 3 month comparative efficacy and safetytreatment period starting at completion of the 6-month main study periodand ending at completion of Month 9 of the main study.

After completion, patients on the adaptable dosing arm may havecontinued this regimen up to the end of the main study (Month 12).Patients injecting HOE901-U300 every 24 hours continued with theirtreatment regimen up to the end of the study.

Duration of Observation:

The analysis period for efficacy and safety is the 3-month study periodstarting at Month 6 of the main study and ending at Month 9 of the mainstudy. Results presented in the present KRM refer to this period.

Criteria for Evaluation:

Efficacy:

Primary Efficacy Endpoint:

change in HbA_(1c) from baseline (Month 6) to endpoint (Month 9).

Secondary Endpoints:

FPG (central laboratory) change from baseline (Month 6) to endpoint(Month 9), daily dose of basal insulin and mealtime insulin.

Safety:

Hypoglycemia, occurrence of adverse events particularlytreatment-emergent adverse events (TEAEs) and serious adverse events(SAEs), injection site reactions and hypersensitivity reactions.Following information not presented in KRM: other safety informationincluding vital signs and overdose.

Statistical Methods: For this 3-month sub-study, Baseline is defined asMonth 6 of the main study period; the Endpoint is month 9 of the Mainstudy.

The primary efficacy endpoint (change in HbA_(1c) from baseline [Month6] to endpoint [Month 9]) was analyzed using an analysis of covariance(ANCOVA) model with treatment regimen and country as fixed effects andusing the HbA_(1c) baseline value as a covariate. Differences betweenHOE901-U300 adaptable dosing regimen and HOE901-U300 fixed dosingregimen and two-sided 95% confidence intervals were estimated within theframework of ANCOVA.

All continuous secondary efficacy variables (except for change invariability of pre-injection SMPG) were analyzed using an ANCOVA modelwith treatment regimen and country as fixed effects and using thecorresponding baseline value as a covariate.

Change in variability of pre-injection SMPG from baseline (month 6) toendpoint (month 9) is analyzed using an analysis of variance (ANOVA)model with treatment regimen and country as fixed effects.

Safety analyses were descriptive, based on the safety population.

Summary:

Population Characteristics:

A total of 110 patients with type 2 diabetes were randomized to thesub-study: 56 patients to the HOE901-U300 adaptable dosing intervalregimen and 54 patients the to HOE901-U300 fixed dosing intervalregimen; 110 patients were exposed to IMP (safety population). The mITTsub-study population (efficacy population) included 109 patients.

One patient (1/56, 1.8%) randomized to HOE901-U300 adaptable dosingintervals discontinued the sub-study prematurely and also discontinuedthe extension period of the main study (HOE901-U300 fixed dosingintervals: 0/54, 0%).

Demographics and patient characteristics at baseline (Month 6) werewell-balanced between both regimen groups. The mean age of the sub-studypopulation was 60 years; 35 of 110 (31.8%) patients were 65 years.

During the sub-study, on average 23.0% of the injections in patients inthe adaptable dosing interval group were taken at the extreme intervalsof <21.5 hours or >26.5 hours from previous injection versus 3.9% ofinjections in patients in the fixed dosing interval group. On average13.5% of the injections in patients in the adaptable dosing intervalgroup were taken in the intermediate interval (between 21.5-23 hours orbetween 25-26.5 hours after the previous injection) versus 8.2% ofinjections in patients in the fixed dosing interval group. Fewerinjections by patients in the adaptable dosing interval group (63.4%)were taken within 23-25 hours after previous injection, compared withthe fixed dosing interval group (88.0%).

A total of 34.5% of patients in the adaptable dosing group took lessthan 20% of their injections outside the 23-25 hours interval afterprevious injection and therefore around 65% of patients were consideredto be compliant with the adaptable dosing interval regimen. In the fixeddosing interval group, 78.8% of patients took more than 80% ofinjections within 23-25 hours from the previous injection and thereforecan be considered to be compliant with the fixed dosing intervalregimen.

The compliance with either regimen was similar when intervals werecalculated from the reference injection time as scheduled at the mainstudy baseline.

Efficacy Results:

Primary Endpoint:

The LS mean change in HbA_(1c) from baseline (Month 6) to endpoint(Month 9) was similar in the groups of adaptable dosing intervals (0.22%[95% CI: −0.006 to 0.436]) and fixed dosing intervals (0.14% [95% CI:−0.099 to 0.380]) with the LS mean difference of 0.07% [95% CI: −0.169to 0.318].

Secondary Efficacy Endpoints (Month 9):

-   -   FPG (adaptable dosing interval 1.40 mmol/L [95% CI: 0.624 to        2.177]; fixed dosing interval (1.18 mmol/L [95% CI: 0.350 to        2.015]; LS mean difference 0.22 mmol/L [95% CI: −0.634 to        1.070]).    -   Pre-injection SMPG, variability of pre-injection SMPG:    -   Adaptation of the injection intervals for HOE901-U300 resulting        in shorter and longer intervals than the regular 24-hour        interval may have an impact on the secondary efficacy endpoints        pre-injection SMPG and variability of pre-injection SMPG.        Therefore in addition to the overall analysis per dosing        interval regimen showing the mean of the average by patient over        up to 7 days prior to the visit, a breakdown of the SMPG data by        injection intervals will be presented in the CSR.

In both dosing interval regimen groups, the average basal and mealtimeinsulin daily doses remained stable during the 3-month comparativeregimen period.

Safety:

During the 3-month comparative regimen period, hypoglycemia events, bothoverall and for each category of hypoglycemia, were reported by asimilar percentage of patients in the HOE901-U300 adaptable dosinginterval and HOE901-U300 fixed dosing interval regimens.

The percentages of patients with any TEAE (adaptable dosing intervals15/56 [26.8%]; fixed dosing intervals 15/54 [27.8%]) or with a seriousTEAE (adaptable dosing intervals 4/56 [7.1%]; fixed dosing intervals5/56 [9.3%]) were comparable between the regimens.

No TEAEs leading to treatment discontinuation, leading to death, orlinked to injection site reactions were observed in either dosinginterval regimen during the 3-month sub-study period. One patient [1.9%]in the fixed dosing interval regimen had a TEAE linked tohypersensitivity reaction.

Conclusions:

The majority of patients in both dosing interval regimen groups followedthe injection schedule as randomized and used either adaptable dosingintervals (HOE901-U300 once daily every 24 hours±3 hours on at least 2days a week) or fixed dosing intervals (HOE901-U300 once daily every 24hours). This allows a comparison of the two dosing interval regimens forefficacy and safety analyses.

The efficacy analyses in terms of HbA1c and FPG showed comparableresults for the two dosing interval regimens.

Overall incidence of hypoglycemia (% of patients with at least oneevent) during the 3-month substudy period was similar in both regimensregardless of the category of hypoglycemia

HOE901-U300 adaptable dosing intervals and HOE901-U300 fixed dosingintervals were well tolerated during the 3-month comparative substudyperiod; no specific safety concerns were observed.

Taken together, according to the substudy results, no negative effectson main efficacy and safety endpoints were seen with occasionaladaptations of injection intervals.

2 Results

2.1 Study Patients

2.1.1 Study disposition

TABLE 43 Patient disposition—Randomized sub-study population HOE901-U300HOE901-U300 Adaptable Dosing Fixed Intervals Dosing Intervals (N = 56)(N = 54) Randomized and treated 56 (100%)  54 (100%) Completed 3-monthcomparative regimen period 55 (98.2%) 54 (100%) Permanently discontinuedthe IMP during the 3-month comparative regimen period 1 (1.8%) 0Subject's request for treatment discontinuation 1 (1.8%) 0 Reason fortreatment discontinuation during the 3-month comparative regimen periodAdverse event 0 0 Lack of efficacy 0 0 Poor compliance to protocol 0 0Other reasons 1 (1.8%) 0 Status at last study contact of patients whopermanently discontinued the treatment during the 3-month comparativeregimen period Alive 1 (1.8%) 0 Dead 0 0 Note: percentages arecalculated using the number of patients randomized as denominator.

TABLE 44 Sub-study analysis populations HOE901-U300 HOE901-U300Adaptable Dosing Fixed Dosing Intervals Intervals All Randomizedsub-study population 56 (100%) 54 (100%) 110 (100%) Efficacy sub-studypopulations Modified Intent-to-Treat (mITT) 55 (98.2%) 54 (100%) 109(99.1%) Sub-study conapleters 55 (98.2%) 54 (100%) 109 (99.1%) Safetysub-study population 56 54 110 Note: patients are tabulated according totheir randomized treatment.

2.1.2 Demographics and Baseline Characteristics

TABLE 45 Demographics and patient characteristics at baseline—Randomizedsub-study population H0E901-U300 HOE901-U300 Adaptable Dosing FixedIntervals Dosing Intervals All (N = 56) (N = 54) (N = 110) Age (years)Number 56   54   110   Mean (SD) 61.0 (7.4)     58.9 (9.6)     60.0(8.6)     Median 61.0 61.0  61.0 Min:Max 40:77 28:74 28:77 Age Group(years) [n (%)] Number 56   54   110   <65 36 (64.3%) 39 (72.2%) 75(68.2%) [65-75[ 18 (32.1%) 15 (27.8%) 33 (30.0%) ≥75 2 (3.6%)  0   2(1.8%) Gender [n (%)] Number 56   54   110   Male 24 (42.9%) 25 (46.3%)49 (44.5%) Female 32 (57.1%) 29 (53.7%) 61 (55.5%) Race [n (%)] Number56   54   110   Caucasian/White 51 (91.1%) 52 (96.3%) 103 (93.6%)  Black5 (8.9%) 1 (1.9%) 6 (5.5%) Asian/Oriental  0   1 (1.9%) 1 (0.9%) Other 0    0     0   Ethnicity [n (%)] Number 56   54   110   Hispanic 4(7.1%) 4 (7.4%) 8 (7.3%) Not Hispanic 52 (92.9%) 50 (92.6%) 102 (92.7%) World region [n (%)] Number 56   54   110   North America 20 (35.7%) 15(27.8%) 35 (31.8%) Western Europe 3 (5.4%) 3 (5.6%) 6 (5.5%) EasternEurope 29 (51.8%) 30 (55.6%) 59 (53.6%) Rest of the world 4 (7.1%)  6(11.1%) 10 (9.1%)  Age is assessed at main study baseline.

TABLE 46 Baseline (month 6) efficacy data related to injectiontime—Randomized sub-study population HOE901-U300 HOE901-U300 AdaptableFixed Dosing Dosing Intervals Intervals All (N = 56) (N = 54) (N = 110)Average injection time from previous injection (hours) Number 56   53  109   Mean (SD) 24.05 (0.49) 24.00 (0.10) 24.02 (0.35) Median 24.0024.00  24.00 Q1:Q3 24.00:24.01 24.00:24.02 24.00:24.01 Min:Max 23.7:27.623.7:24.2 23.7:27.6 Average injection time from reference injection(hours) Number 56   53   109   Mean (SD) 24.03 (0.60) 24.20 (0.63) 24.11(0.62) Median 24.00 24.00  24.00 Q1:Q3 23.93:24.25 23.95:24.6823.94:24.44 Min:Max 21.5:26.3 22.2:25.6 21.5:26.3 Average: mean intervalvalue over at least 3 times intervals during the last 7 days precedingmonth 6.

2.1.3 Measurement of Treatment Compliance

TABLE 47 Compliance—Dosing regimen compliance during the 3-monthcomparative regimen period—Percentage of injections (time from previousinjection) by dosing interval category—Safety sub-study populationHOE901-U300 HOE901-U300 Adaptable Dosing Fixed Intervals DosingIntervals % of injections by patient (N = 56) (N = 54) <21.5 hoursor >26.5 hours Number 55     52    Mean (SD) 23.02 (26.62) 3.85 (10.97)Median 16.67   0.00 Q1:Q3  0.00:36.36 0.00:0.00 Min:Max   0.0:100.0 0.0:46.2 [23-25] hours Number 55     52    Mean (SD) 63.44 (26.60)87.96 (22.01)  Median 66.67 100.00 Q1:Q3 41.67:83.33  83.33:100.00Min:Max   0.0:100.0  16.7:100.0 [21.5-23[hours or]25-26.5] hours Number55     52    Mean (SD) 13.54 (15.23) 8.19 (16.11) Median  8.33   0.00Q1:Q3  0.00:25.00 0.00:8.71 Min:Max  0.0:58.3  0.0:66.7 Note: Percentageof injections (time from previous injection) in each dosing intervalcategory is calculated for each patient using all intervals obtainedduring the last 7 days values before Month 7.5 and Month 9 visits. Note:Only patients with at least 3 time intervals during the last 7 daysvalues before Month 7.5 or Month 9 visits are considered for this table.

TABLE 48 Compliance—Number of patients for whom less than 20% ofinjections are outside the 23 to 25-hour time window from the previousinjection time—Safety sub-study population HOE901-U300 AdaptableHOE901-U300 Dosing Fixed Dosing Intervals Intervals (N = 56) (N = 54)Patients for whom less than 20% of 19/55 (34.5%) 41/52 (78.8%)injections are outside the 23 to 25-hour time window from the previousinjection time Note: Percentage of injections (time from previousinjection) is calculated using all intervals obtained during the last 7days values before Month 7.5 and Month 9 visits. Note: Only patientswith at least 3 time intervals during the last 7 days values beforeMonth 7.5 or Month 9 visits are considered for this table.

TABLE 49 Compliance—Dosing regimen compliance during the 3-monthcomparative regimen period—Percentage of injections (time from referenceinjection) by dosing interval category—Safety sub-study populationHOE901-U300 HOE901-U300 Adaptable Dosing Fixed Intervals DosingIntervals % of injections by patient (N = 56) (N = 54) <21.5 hoursor >26.5 hours Number 55    52   Mean (SD) 17.27 (19.25) 0.82 (3.05)Median 14.29   0.00 Q1:Q3  0.00:28.57 0.00:0.00 Min:Max  0.0:64.3 0.0:14.3 [23-25] hours Number 55    52   Mean (SD) 64.96 (25.45) 83.52(25.22) Median 71.43 100.00 Q1:Q3 50.00:85.71  75.65:100.00 Min: Max  0.0:100.0   0.0:100.0 [21.5-23[hours or ]25-26.5] hours Number 55   52   Mean (SD) 17.77 (19.40) 15.65 (24.67) Median 14.29   0.00 Q1:Q30.00:28.57  0.00:21.43 Min: Max  0.0:78.6   0.0:100.0 Note: Percentageof injections (time from reference injection chosen at the start of themain study) in each dosing interval category is calculated for eachpatient using all intervals obtained during the last 7 days valuesbefore Month 7.5 and Month 9 visits. Note: Only patients with at least 3time intervals during the last 7 days values before Month 7.5 or Month 9visits are considered for this table.

2.2 Efficacy Evaluation

2.2.1 Primary Efficacy Endpoint

TABLE 50 Main efficacy analysis-Mean change in HbA1c (%) from baseline(month 6) to Month 9 endpoint using LOCF procedure-mITT sub-studypopulation HOE901-U300 Adaptable HOE901-U300 Fixed Dosing IntervalsDosing Intervals HbA1c (%) (N = 55) (N = 54) Baseline (month 6) Number55 52 Mean (SD) 7.21 (0.91) 7.17 (0.88) Median 7.10 7.00 Min:Max 5.7:10.6 5.7:9.4 Month 9 endpoint (LOCF) Number 55 52 Mean (SD) 7.25(0.96) 7.12 (0.96) Median 7.10 6.80 Min:Max 5.5:9.9  5.8:10.7 Changefrom baseline to Month 9 endpoint (LOCF) Number 55 52 Mean (SD) 0.03(0.56) −0.05 (0.72)   Median 0.00 0.00 Min:Max −1.4:1.4   −2.8:1.8   LSMean (SE) ^(a)  0.22 (0.111)  0.14 (0.121) 95% CI (−0.006 to 0.436)(−0.099 to 0.380) LS Mean difference (SE) vs. HOE901-U300 Fixed Dosingintervals ^(a)  0.07 (0.123) 95% CI (−0.169 to 0.318) LOCF = Lastobservation carried forward. ^(a) Analysis of covariance (ANCOVA) modelwith treatment regimen and country as fixed effects and baseline HbA1cvalue as a covariate.

The Mean HbA1c (%) by Visit During the 3-Month Comparative RegimenPeriod—mITT Sub-Study Population is Described in FIG. 9.

2.2.2 Secondary Endpoints

2.2.2.1 Fasting Plasma Glucose

TABLE 51 Mean change in FPG (mmol/L) from baseline (month 6) to Month 9endpoint using LOCF procedure-mITT sub-study population HOE901-U300Adaptable HOE901-U300 Fixed Dosing Intervals Dosing Intervals FPG(mmol/L) (N = 55) (N = 54) Baseline (month 6) Number 54 51 Mean (SD)7.33 (2.09) 6.78 (2.58) Median 7.20 6.50 Min:Max 2.4:11.4 2.5:15.3 Month9 endpoint (LOCF) Number 54 51 Mean (SD) 7.61 (2.38) 7.07 (3.06) Median7.25 6.60 Min:Max 3.7:14.0 3.0:20.6 Change from baseline to Month 9endpoint (LOCF) Number 54 51 Mean (SD) 0.28 (2.46) 0.29 (2.31) Median0.45 0.20 Min:Max −5.0:7.7    −5.8:9.1    LS Mean (SE) ^(a)  1.40(0.391)  1.18 (0.419) 95% CI (0.624 to 2.177) (0.350 to 2.015) LS Meandifference (SE) vs. HOE901-U300 Fixed Dosing Intervals ^(a)  0.22(0.429) 95% CI (−0.634 to 1.070)   FPG = Fasting Plasma Glucose. LOCF =Last observation carried forward. ^(a) Analysis of covariance (ANCOVA)model with treatment regimen and country as fixed effects and baselineFPG value as a covariate.

2.2.2.2 Basal and Mealtime Insulin Dose

The Average Daily Basal (Glargine) and Mealtime Insulin Dose (U) byVisit During the 3-Month Comparative Regimen Period—mITT Sub-StudyPopulation is Described in FIG. 10.

2.3 Safety Evaluation

2.3.1 Extent of Exposure

TABLE 52 Exposure to investigational product during the 3-monthcomparative regimen period-Safety sub-study population HOE901-U300Adaptable Dosing HOE901-U300 Fixed Intervals Dosing Intervals (N = 56)(N = 54) Cumulative exposure to the sub-study 3-month 13.82 13.38treatment (patient years) Duration of the sub-study 3-month treatment(days) Number 55 53 Mean (SD) 91.8 (4.9) 92.2 (6.2) Median 92.0 92.0Min:Max 77:112 83:126 Duration of the sub-study 3-month treatment bycategory [n(%)] Missing duration 1 (1.8%) 1 (1.9%) up to 6 weeks 0 0 >6to 12 weeks 2 (3.6%) 3 (5.6%) >12 weeks 53 (94.6%) 50 (92.6%) Cumulativeduration of the sub-study 3-month treatment by category [n(%)] Missingduration 1 (1.8%) 1 (1.9%) ≥1 days 55 (98.2%) 53 (98.1%)  >6 weeks 55(98.2%) 53 (98.1%) >12 weeks 53 (94.6%) 50 (92.6%)

2.3.2 Hypoglycemia

TABLE 53 Number (%) of patients with at least one hypoglycemia eventduring the 3-month comparative regimen period-Safety sub-studypopulation Nocturnal hypoglycemia All hypoglycemia (00:00-05:59)HOE901-U300 HOE901-U300 Adaptable HOE901-U300 Adaptable HOE901-U300Dosing Fixed Dosing Dosing Fixed Dosing Intervals Intervals IntervalsIntervals Type of hypoglycemia event n(%) (N = 56) (N = 54) (N = 56) (N= 54) Any hypoglycemia event 32 (57.1%) 36 (66.7%) 15 (26.8%) 13 (24.1%)Severe hypoglycemia 0 1 (1.9%) 0 1 (1.9%) Documented symptomatichypoglycemia ≤3.9 mmol/L (70 mg/dL) 18 (32.1%) 23 (42.6%) 11 (19.6%)  9(16.7%) <3.0 mmol/L (54 mg/dL) 11 (19.6%) 12 (22.2%) 3 (5.4%)  6 (11.1%)Asymptomatic hypoglycemia ≤3.9 mmol/L (70 mg/dL) 22 (39.3%) 24 (44.4%) 3(5.4%)  6 (11.1%) <3.0 mmol/L (54 mg/dL) 2 (3.6%)  6 (11.1%) 1 (1.8%) 1(1.9%) Probable symptomatic hypoglycemia 1 (1.8%) 0 0 0 Relativehypoglycemia >3.9 mmol/L (70 mg/dL) 3 (5.4%) 0 1 (1.8%) 0 Severe and/orconfirmed^(a) hypoglycemia ≤3.9 mmol/L (70 mg/dL) 31 (55.4%) 36 (66.7%)14 (25.0%) 13 (24.1%) <3.0 mmol/L (54 mg/dL) 13 (23.2%) 16 (29.6%) 4(7.1%)  8 (14.8%) n (%) = number and percentage of patients with atleast one hypoglycemia event. ^(a)Severe and/or confirmed hypoglycemia =severe and/or confirmed by plasma glucose <= 3.9 mmol/L (70 mg/dL)(resp. <3.0 mmol/L (54 mg/dL)). Note: All hypoglycemia events withmissing time are counted in the column “All hypoglycemia”, but notclassified as “nocturnal” or “daytime”.)

2.3.3 Treatment-Emergent Adverse Events

TABLE 54 Treatment emergent adverse events during the 3-monthcomparative regimen period-Safety sub-study population HOE901-U300Adaptable HOE901-U300 Fixed Dosing Intervals Dosing Intervals n (%) (N =56) (N = 54) Patients with any TEAE 15 (26.8%) 15 (27.8%) Patients withany treatment emergent SAE 4 (7.1%) 5 (9.3%) Patients with any TEAEleading to death 0 0 Patients with any TEAE leading to permanenttreatment 0 0 discontinuation TEAE: Treatment emergent adverse event,SAE: Serious Adverse Event. n (%) = number and percentage of patientswith at least one TEAE.

TABLE 55 Number (%) of patients with TEAE(s) by primary SOC, HLGT, HLTand PT events during the 3-month comparative regimen period-Safetysub-study population PRIMARY SYSTEM ORGAN CLASS HLGT: High Level GroupTerm HOE901-U300 Adaptable HOE901-U300 Fixed HLT: High Level Term DosingIntervals Dosing Intervals Preferred Term n(%) (N = 56) (N = 54) Anyclass 15 (26.8%) 15 (27.8%) INFECTIONS AND INFESTATIONS  7 (12.5%) 4(7.4%) HLGT: Bacterial infectious disorders 2 (3.6%) 0 HLT: Bacterialinfections NEC 1 (1.8%) 0 Conjunctivitis bacterial 1 (1.8%) 0 HLT:Staphylococcal infections 1 (1.8%) 0 Staphylococcal infection 1 (1.8%) 0HLGT: Infections-pathogen unspecified  6 (10.7%) 3 (5.6%) HLT: Abdominaland gastrointestinal infections 0 1 (1.9%) Gastroenteritis 0 1 (1.9%)HLT: Bone and joint infections 1 (1.8%) 0 Osteomyelitis 1 (1.8%) 0 HLT:Infections NEC 2 (3.6%) 0 Localised infection 1 (1.8%) 0 Postoperativewound infection 1 (1.8%) 0 HLT: Lower respiratory tract and lunginfections 1 (1.8%) 0 Bronchitis 1 (1.8%) 0 HLT: Upper respiratory tractinfections 2 (3.6%) 2 (3.7%) Nasopharyngitis 2 (3.6%) 1 (1.9%) Upperrespiratory tract infection 0 1 (1.9%) HLGT: Viral infectious disorders1 (1.8%) 1 (1.9%) HLT: Influenza viral infections 1 (1.8%) 0 Influenza 1(1.8%) 0 HLT: Viral infections NEC 0 1 (1.9%) Gastroenteritis viral 0 1(1.9%) NEOPLASMS BENIGN, MALIGNANT AND 0 1 (1.9%) UNSPECIFIED (INCLCYSTS AND POLYPS) HLGT: Reproductive neoplasms female benign 0 1 (1.9%)HLT: Uterine neoplasms benign 0 1 (1.9%) Uterine leiomyoma 0 1 (1.9%)HLGT: Reproductive neoplasms female malignant 0 1(1.9%) and unspecifiedHLT: Endometrial neoplasms malignant 0 1 (1.9%) Endometrial cancer 01(1.9%) METABOLISM AND NUTRITION DISORDERS 1 (1.8%) 0 HLGT: Glucosemetabolism disorders (incl diabetes 1 (1.8%) 0 mellitus) HLT:Hyperglycaemic conditions NEC 1 (1.8%) 0 Hyperglycaemia 1 (1.8%) 0NERVOUS SYSTEM DISORDERS 1 (1.8%) 1 (1.9%) HLGT: Headaches 1 (1.8%) 0HLT: Headaches NEC 1 (1.8%) 0 Headache 1 (1.8%) 0 HLGT: Neurologicaldisorders NEC 1 (1.8%) 1 (1.9%) HLT: Nervous system disorders NEC 1(1.8%) 0 Nervous system disorder 1 (1.8%) 0 HLT: Neurological signs andsymptoms NEC 1 (1.8%) 1 (1.9%) Dizziness 1 (1.8%) 1 (1.9%) EYE DISORDERS0 1 (1.9%) HLGT: Ocular infections, irritations and 0 1 (1.9%)inflammations HLT: Lid, lash and lacrimal infections, irritations 0 1(1.9%) and inflammations Eyelid cyst 0 1 (1.9%) CARDIAC DISORDERS 2(3.6%) 0 HLGT: Cardiac disorder signs and symptoms 1 (1.8%) 0 HLT:Cardiac signs and symptoms NEC 1 (1.8%) 0 Palpitations 1 (1.8%) 0 HLGT:Coronary artery disorders 2 (3.6%) 0 HLT: Coronary artery disorders NEC1 (1.8%) 0 Coronary artery disease 1 (1.8%) 0 HLT: Ischaemic coronaryartery disorders 1 (1.8%) 0 Angina pectoris 1(1.8%) 0 RESPIRATORY,THORACIC AND MEDIASTINAL 3 (5.4%) 2 (3.7%) DISORDERS HLGT: Bronchialdisorders (excl neoplasms) 0 1 (1.9%) HLT: Bronchospasm and obstruction0 1 (1.9%) Asthma 0 1 (1.9%) HLGT: Respiratory disorders NEC 3 (5.4%) 0HLT: Breathing abnormalities 1 (1.8%) 0 Sleep apnoea syndrome 1 (1.8%) 0HLT: Coughing and associated symptoms 2 (3.6%) 0 Cough 2 (3.6%) 0 HLT:Upper respiratory tract signs and symptoms 1 (1.8%) 0 Oropharyngeal pain1 (1.8%) 0 HLGT: Upper respiratory tract disorders (excl 0 1 (1.9%)infections) HLT: Nasal congestion and inflammations 0 1 (1.9%) Nasalcongestion 0 1 (1.9%) GASTROINTESTINAL DISORDERS 3 (5.4%) 3 (5.6%) HLGT:Benign neoplasms gastrointestinal 1 (1.8%) 0 HLT: Benign neoplasmsgastrointestinal (excl 1 (1.8%) 0 oral cavity) Large intestine polyp1(1.8%) 0 HLGT: Gastrointestinal motility and defaecation 0 3 (5.6%)conditions HLT: Diarrhoea (excl infective) 0 3 (5.6%) Diarrhoea 0 3(5.6%) HLGT: Gastrointestinal signs and symptoms 2 (3.6%) 0 HLT: Nauseaand vomiting symptoms 2 (3.6%) 0 Nausea 1 (1.8%) 0 Vomiting 1 (1.8%) 0HEPATOBILIARY DISORDERS 0 1 (1.9%) HLGT: Bile duct disorders 0 1 (1.9%)HLT: Obstructive bile duct disorders (excl 0 1 (1.9%) neoplasms) Bileduct stone 0 1 (1.9%) MUSCULOSKELETAL AND CONNECTIVE TISSUE 4 (7.1%) 3(5.6%) DISORDERS HLGT: Joint disorders 2 (3.6%) 1 (1.9%) HLT:Osteoarthropathies 2 (3.6%) 0 Osteoarthritis 1 (1.8%) 0 Spinalosteoarthritis 1 (1.8%) 0 HLT: Spondyloarthropathies 0 1 (1.9%)Spondylitis 0 1 (1.9%) HLGT: Musculoskeletal and connective tissue 0 1(1.9%) deformities (incl intervertebral disc disorders) HLT:Intervertebral disc disorders NEC 0 1 (1.9%) Intervertebral discprotrusion 0 1 (1.9%) HLGT: Musculoskeletal and connective tissue 2(3.6%) 0 disorders NEC HLT: Musculoskeletal and connective tissue pain 2(3.6%) 0 and discomfort Musculoskeletal pain 1 (1.8%) 0 Pain inextremity 1 (1.8%) 0 HLGT: Synovial and bursal disorders 0 1 (1.9%) HLT:Synovial disorders 0 1 (1.9%) Synovial cyst 0 1 (1.9%) REPRODUCTIVESYSTEM AND BREAST 0 1 (1.9%) DISORDERS HLGT: Menopause and relatedconditions 0 1 (1.9%) HLT: Menopausal effects on the genitourinary 0 1(1.9%) tract Postmenopausal haemorrhage 0 1 (1.9%) GENERAL DISORDERS ANDADMINISTRATION 1 (1.8%) 0 SITE CONDITIONS HLGT: General system disordersNEC 1 (1.8%) 0 HLT: Oedema NEC 1 (1.8%) 0 Oedema peripheral 1 (1.8%) 0INVESTIGATIONS 0 1 (1.9%) HLGT: Renal and urinary tract investigationsand 0 1 (1.9%) urinalyses HLT: Renal function analyses 0 1 (1.9%) Bloodcreatinine increased 0 1 (1.9%) INJURY, POISONING AND PROCEDURAL 3(5.4%) 3 (5.6%) COMPLICATIONS HLGT: Bone and joint injuries 0 1 (1.9%)HLT: Upper limb fractures and dislocations 0 1 (1.9%) Humerus fracture 01 (1.9%) HLGT: Exposures, chemical injuries and poisoning 0 1 (1.9%)HLT: Poisoning and toxicity 0 1 (1.9%) Toxicity to various agents 0 1(1.9%) HLGT: Injuries NEC 1 (1.8%) 0 HLT: Muscle, tendon and ligamentinjuries 1 (1.8%) 0 Ligament sprain 1 (1.8%) 0 HLGT: Procedural relatedinjuries and complications 2 (3.6%) 1 (1.9%) NEC HLT: Gastrointestinaland hepatobiliary 0 1 (1.9%) procedural complications Abdominal wounddehiscence 0 1 (1.9%) HLT: Non-site specific procedural complications 2(3.6%) 0 Procedural pain 2 (3.6%) 0 TEAE: Treatment emergent adverseevent, SOC: System organ class, HLGT: High level group term, HLT: Highlevel term, PT: Preferred term. MedDRA 16.0. n(%) = number andpercentage of patients with at least one TEAE. Note: Table sorted by SOCinternationally agreed order and HLGT, HLT, PT by alphabetic order.

2.3.4 Serious Treatment-Emergent Adverse Events

TABLE 56 Number (%) of patients with treatment emergent SAE(s) byPrimary SOC, HLGT, HLT and PT during the 3-month comparative regimenperiod-Safety sub-study population PRIMARY SYSTEM ORGAN CLASS HLGT: HighLevel Group Term HOE901-U300 Adaptable HOE901-U300 Fixed HLT: High LevelTerm Dosing Intervals Dosing Intervals Preferred Term n(%) (N = 56) (N =54) Any class 4 (7.1%) 5 (9.3%) INFECTIONS AND INFESTATIONS 2 (3.6%) 0HLGT: Infections-pathogen unspecified 2 (3.6%) 0 HLT: Bone and jointinfections 1 (1.8%) 0 Osteomyelitis 1 (1.8%) 0 HLT: Infections NEC 1(1.8%) 0 Postoperative wound infection 1 (1.8%) 0 NEOPLASMS BENIGN,MALIGNANT AND 0 1 (1.9%) UNSPECIFIED (INCL CYSTS AND POLYPS) HLGT:Reproductive neoplasms female benign 0 1 (1.9%) HLT: Uterine neoplasmsbenign 0 1 (1.9%) Uterine leiomyoma 0 1 (1.9%) HLGT: Reproductiveneoplasms female malignant 0 1 (1.9%) and unspecified HLT: Endometrialneoplasms malignant 0 1 (1.9%) Endometrial cancer 0 1 (1.9%) CARDIACDISORDERS 1 (1.8%) 0 HLGT: Coronary artery disorders 1 (1.8%) 0 HLT:Coronary artery disorders NEC 1 (1.8%) 0 Coronary artery disease 1(1.8%) 0 RESPIRATORY, THORACIC AND MEDIASTINAL 0 1 (1.9%) DISORDERSHLGT: Bronchial disorders (excl neoplasms) 0 1 (1.9%) HLT: Bronchospasmand obstruction 0 1 (1.9%) Asthma 0 1 (1.9%) HEPATOBILIARY DISORDERS 0 1(1.9%) HLGT: Bile duct disorders 0 1 (1.9%) HLT: Obstructive bile ductdisorders (excl 0 1 (1.9%) neoplasms) Bile duct stone 0 1 (1.9%)MUSCULOSKELETAL AND CONNECTIVE TISSUE 0 2 (3.7%) DISORDERS HLGT: Jointdisorders 0 1 (1.9%) HLT: Spondyloarthropathies 0 1 (1.9%) Spondylitis 01 (1.9%) HLGT: Synovial and bursal disorders 0 1 (1.9%) HLT: Synovialdisorders 0 1 (1.9%) Synovial cyst 0 1 (1.9%) REPRODUCTIVE SYSTEM ANDBREAST 0 1 (1.9%) DISORDERS HLGT: Menopause and related conditions 0 1(1.9%) HLT: Menopausal effects on the genitourinary 0 1 (1.9%) tractPostmenopausal haemorrhage 0 1 (1.9%) INJURY, POISONING AND PROCEDURAL 1(1.8%) 2 (3.7%) COMPLICATIONS HLGT: Bone and joint injuries 0 1 (1.9%)HLT: Upper limb fractures and dislocations 0 1 (1.9%) Humerus fracture 01 (1.9%) HLGT: Procedural related injuries and complications 1 (1.8%) 1(1.9%) NEC HLT: Gastrointestinal and hepatobillary 0 1 (1.9%) proceduralcomplications Abdominal wound dehiscence 0 1 (1.9%) HLT: Non-sitespecific procedural complications 1 (1.8%) 0 Procedural pain 1 (1.8%) 0TEAE: Treatment emergent adverse event, SOC: System organ class, HLGT:High level group term, HLT: High level term, PT: Preferred term. MedDRA16.0. n (%) = number and percentage of patients with at least onetreatment emergent SAE. Note: Table sorted by SOC internationally agreedorder and HLGT, HLT, PT by alphabetic order.

2.3.5 Treatment Emergent Adverse Events Leading to Withdrawal

TABLE 57 Number (%) of patients with TEAE(s) leading to permanenttreatment discontinuation by Primary SOC, HLGT, HLT and PT during the 3-month comparative regimen period-Safety sub-study population No dataTEAE: Treatment emergent adverse event, SOC: System organ class, HLGT:High level group term, HLT: High level term, PT: Preferred team MedDRA16.0. n (%) = number and percentage of patients with at least one TEAEleading to permanent treatment discontinuation. Note: Table sorted bySOC internationally agreed order and HLGT, HLT, PT by alphabetic order.

2.3.6 Other Significant Treatment Emergent Adverse Events

2.3.6.1 Injection Site Reactions

TABLE 58 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term-Injection sitereactions during the 3-month comparative regimen period-Safety sub-studypopulation No data TEAE: Treatment emergent adverse event, PT: Preferredterm. MedDRA 16.0 n (%) = number and percentage of patients with atleast one injection site reactions TEAE. Note: Table sorted bydecreasing frequency of PT in HOE901-U300 adaptable dosing intervalsregimen.

2.3.6.2 Hypersensitivity Reactions

TABLE 59 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term-Hypersensitivity reactions during the 3-month comparative regimenperiod-Safety sub-study population HOE901-U300 HOE901-U300 AdaptableFixed Dosing Intervals Dosing Intervals Preferred Term (N = 56) (N = 54)Any hypersensitivity reactions 0 1 (1.9%) Asthma 0 1 (1.9%) TEAE:Treatment emergent adverse event, PT: Preferred term. MedDRA 16.0 n (%)= number and percentage of patients with at least one hypersensitivityreactions TEAE. Note: Table sorted by decreasing frequency of PT inHOE901-U300 adaptable dosing intervals regimen.

EXAMPLE 4: 16-WEEK, RANDOMIZED, OPEN-LABEL, CONTROLLED STUDY COMPARINGTHE EFFICACY AND SAFETY OF A NEW FORMULATION OF INSULIN GLARGINE VERSUSLANTUS IN PATIENTS WITH TYPE 1 DIABETES MELLITUS

Phase of Development:

2

Objectives:

Primary objective: To compare the glucose control during treatment witha new formulation of insulin glargine (HOE901-U300) and Lantus in adultpatients with type 1 diabetes mellitus.

Secondary objectives:

-   -   To compare HOE901-U300 and Lantus given in the morning or in the        evening regarding the continuous glucose monitoring (CGM) data:        diurnal glucose exposure; diurnal glucose stability as measured        by rate of change in median curve; diurnal glucose variability        as measured by interquartile range (IQR); mean and variation in        glucose profiles    -   To compare HOE901-U300 and Lantus regarding glycated hemoglobin        A1c (HbA1c), self-measured plasma glucose (fasting plasma        glucose, prior to injection of study drug, 7-point profiles)    -   To compare the incidence and frequency of hypoglycemic episodes        classified as defined by ADA criteria, both symptomatic,        confirmed by plasma glucose £70 mg/dL and CGM-detected    -   To assess the safety and tolerability of HOE901-U300

Methodology:

Multicenter, open-label, randomized, 4-arm parallel-group, comparativePhase 2 study comparing HOE901-U300 and Lantus in patients with type 1diabetes mellitus. Patients were randomized to receive once daily basalinsulin (HOE901-U300 or Lantus) and to the sequence of the injectiontime during study period A and study period B (morning then evening orevening then morning) with a ratio of 1:1:1:1. No formal sample sizeestimation was performed for this exploratory study.

Number of Patients:

planned 56, randomized 59, treated 59, Evaluated: efficacy 59, safety 59

Diagnosis and Criteria for Inclusion:

Inclusion criteria: Patients with type 1 diabetes mellitus; signedwritten informed consent. Key exclusion criteria: Age <18 years and >70years; HbA1c >9% at screening; less than 1 year on basal plus mealtimeinsulin; Patients receiving >0.5 U/kg body weight basal insulin andpatients not on stable insulin dose (±20% total basal insulin dose) inthe last 30 days prior to screening visit; Hospitalization for diabeticketoacidosis or history of severe hypoglycemia (requiring 3rd partyassistance) in the last 6 months prior to randomization.

Study Treatments

Investigational Medicinal Products:

Tested drug: HOE901-U300; Control drug: Lantus

Formulations: HOE901-U300 was supplied as 300 U/mL insulin glarginesolution for subcutaneous (SC) injection in 3 mL cartridges. Lantus wassupplied as insulin glargine solution for SC injection 100 U/mL in 10 mLvials.

Route of administration: SC injection

Injection of HOE901-U300 was through the commercially available BDUltra-Fine™ Short Needle Insulin Syringe with half-unit-scale. Injectionof Lantus was to be done using commercially available BD insulinsyringes:

-   -   for doses of 1-30 U insulin glargine: BD Ultra-Fine™ Short        Needle Insulin Syringe with half-unit-scale [8 mm (5/16″)×31 G];    -   for doses >30 U insulin glargine: BD Ultra-Fine™ Short Needle        Insulin Syringe [8 mm ( 5/16″)×31 G] with whole unit scale.

Dose regimen: Once daily injection in the morning or evening for 8 weeksduring Period A then in the evening or morning respectively for another8 weeks during Period B according to randomization.

Starting dose: Patients on Lantus or on once daily NPH or once dailyinsulin detemir prior to the baseline visit: the daily dose (U) ofHOE901-U300 or Lantus was equal to the daily basal insulin doses on theday prior to the baseline visit. Patients on more than once daily NPH orinsulin detemir prior to the baseline visit: 80% of total daily NPH orinsulin detemir dose (=total daily dose reduced by 20%) on the day priorto the baseline visit.

Doses during the study: Dosing of insulin glargine given as HOE901-U300or Lantus was done based on self-measured, fasting, pre breakfast plasmaglucose levels (target range 80-130 mg/dL; 4.4-7.2 mmol/L), and takinginto account also the presence of hypoglycemia. Minimum dose incrementsfor the basal insulin were to be 1.5 U. Batch number: HOE901—U300:C1011129; Lantus: supplied by local pharmacies.

Non-Investigational Medicinal Products:

Short-acting mealtime (bolus) insulin analogue (glulisine, aspart orlispro).

Patients in both treatment groups were to continue with their mealtimeinsulin analogue during the study.

Mealtime insulin doses were to be adjusted based on SMPG data, including2-hour postprandial plasma glucose results and the carbohydrate contentof the meal to optimize glycemic control. The target range for 2-hourpostprandial plasma glucose was <160 mg/dL (8.3 mmol/L). Bolus insulindoses could be reduced as basal insulin doses were increased.

Duration of Treatment:

Up to 16 weeks (8 weeks during Period A and 8 weeks during Period B)

Duration of Observation:

-   -   Up to 4-week screening (including a 2-week CGM training period);    -   2×8-week comparative efficacy and safety treatment period;    -   4 week post-treatment safety follow-up period after study        completion or permanent discontinuation of study treatment.

In total the maximum study duration was up to 24 weeks per patient

Criteria for Evaluation:

Efficacy

Primary Efficacy Endpoint:

Percent (%) of time in glycemic range of 80-140 mg/dL (4.4-7.8 mmol/L)during week 7 and 8 within treatment period A and during week 15 and 16in treatment period B based on CGM.

Secondary Efficacy Endpoints:

Percent time above upper limit/below lower limit of glycemic range (%time in hyperglycemia/hypoglycemia).

The following secondary efficacy endpoints are not presented in thisKRM: Diurnal glucose exposure; Diurnal glucose stability; Diurnalglucose variability; Mean and variation in glucose profiles; Averagetime within glycemic range in the last four hours of each dosinginterval during 14 days of CGM usage in the last 2 weeks of the 8 weekstreatment period; Hyperglycemic AUC (Area below the CGM profile andabove the upper limit of the glycemic range divided by total timeperiod); and hypoglycemic AUC (Area above the CGM profile and below thelower limit of the glycemic range divided by total time period.

Further Secondary Efficacy Endpoints:

insulin dose; Not presented in this KRM: HbA_(1c), fasting plasmaglucose (FPG), pre-injection SMPG, 7-point SMPG.

Safety

Hypoglycemia, occurrence of adverse events particularly treatmentemergent adverse events (TEAEs) and serious adverse events (SAEs),injection site reactions and hypersensitivity reactions. Followinginformation not presented in KRM: physical examination, other safetyinformation including clinical laboratory data, vital signs and 12-leadECG.

Statistical Methods:

The primary endpoint was analyzed using a linear mixed model withtreatment (HOE901-U300 or Lantus) and period (treatment period A or B)as fixed effects, and patient as random effect. Adjusted mean estimatesfor each treatment with standard errors, the adjusted estimate oftreatment mean difference with standard error and a 95 confidenceinterval for the treatment mean difference will be provided. Thestatistical test was two-sided tests at a nominal 5% significance level.The same model was used for secondary efficacy endpoints % time inhyperglycemia/hypoglycemia, diurnal glucose exposure, diurnal glucosestability and diurnal glucose variability. Other efficacy endpoints weredescriptive. CGM related parameters were analyzed based on CGMpopulation, non-CGM parameters were based on mITT population.

Safety analyses were descriptive, based on the safety population.

Summary:

Population Characteristics:

A total of 59 patients with type 1 diabetes were randomized to 1 of 4arms: HOE901-U300 morning injection in Period A followed by eveninginjection in Period B (n=15), HOE901-U300 evening then morning injection(n=15), Lantus morning then evening injection (n=15), or Lantus eveningthen morning injection (n=14). A total of 59 patients were exposed toIMP (safety population) and included in the mITT and CGM populations(efficacy populations). One patient (3.3%) in the HOE901-U300 group and3 patients (10.3%) in the Lantus group discontinued the study treatmentprematurely. Demographics and baseline characteristics were balancedbetween treatment groups. The mean age of the study population was 44.2years, 2 patients were 65 years or older. All patients were Caucasian.The mean BMI at baseline was 27.3 kg/m². The mean duration of diabetesprior to study start was 22.1 years. The median dose of daily totalinsulin was 0.565 U/kg body weight. Mean HbA_(1c) at baseline was 7.46%.

Efficacy Results:

Primary Efficacy Endpoint:

During the last 2 weeks of each 8-week treatment period, when the basalinsulin dose was to be kept as stable as possible, plasma glucosemeasured by CGM was observed within glycemic range in 31.75% (LS mean)of time in the HOE901-U300 group and in 30.99% (LS mean) of time in theLantus group. The LS mean difference was 0.75% [95% CI: −3.614 to5.124].

Secondary Efficacy Endpoints:

During the last 2 weeks of each 8-week treatment period, percent timeabove the upper limit of glycemic range of 140 mg/dL (7.8 mmol/L) wascomparable between treatment groups (58.24% in the HOE901-U300 group and57.38% in the Lantus group in LS mean), so was the percent of time belowthe lower limit of 80 mg/dL (4.4 mmol/L) with 10.01% in the HOE901-U300group and 11.64% in the Lantus group in LS mean.

Graphical presentation of average glucose based on CGM by hour of theday during the entire treatment period (FIG. 11) suggests smallerexcursions in the HOE901-U300 group than in the Lantus group. Theprofile appears flatter with HOE901-U300 than with Lantus even moreduring morning injection period (FIG. 12) than during evening injectionperiod (FIG. 13).

Overall, in the HOE901-U300 and in the Lantus treatment groups, basalinsulin was similarly increased mostly in the first 6 weeks of the studyand remained relatively stable thereafter (at baseline, mean daily basalinsulin dose was similar in both treatment groups: HOE901-U300: 24.9units; Lantus: 25.0 units; at week 16, HOE901-U300: 30.11 units; Lantus:28.22 units).

Mean mealtime insulin daily dose was higher at baseline in theHOE901-U300 group (29.92 units) than in the Lantus group (23.69 units),but was comparable at week 16 (HOE901-U300: 27.34 units; Lantus: 26.31units).

Safety Results:

During the on-treatment period, the percentages of patients experiencinghypoglycemia were generally comparable for overall and each category ofhypoglycemia events (all hypoglycemia) in the HOE901-U300 group and theLantus group. Consistently, similarity was observed in the hypoglycemiareporting between the following subgroups:

-   -   the morning and evening injection groups within the HOE901-U300        group;    -   the morning and evening injection groups within the Lantus        group;    -   the HOE901-U300 morning injection groups and the Lantus morning        injection groups;    -   the HOE901-U300 evening injection groups and the Lantus evening        injection groups;

The percentages of patients experiencing nocturnal hypoglycemia wereconsistently lower in the HOE901-U300 group than in the Lantus groupregardless of morning or evening injection time. The favorable numericaltrends in the HOE901-U300 group have to be interpreted with cautionbecause of the small number of patients.

The percentage of patients with any TEAEs was higher in the HOE901-U300group (24/30 [80.0%]) than in the Lantus group (19/29 [65.5%]). In theHOE901-U300 group, one patient experienced serious intestinalobstruction (unrelated to IMP) and another patient discontinuedtreatment due to pregnancy. No death was reported during the study.TEAEs linked to injection site reactions were observed in 2/30 [6.7%]patients of the HOE901-U300 group, and in 1/29 [3.4%] patient of theLantus group. There is no concern regardingTEAEs linked tohypersensitivity reaction which occurred in 4/40 patients of theHOE901-U300 group and in 1/30 patient of the Lantus group.

Conclusions:

Plasma glucose measured by CGM was observed within glycemic target range(80-140 mg/dL or 4.4-7.8 mmol/L) for a similar percentage of time duringthe last 2 weeks of each 8-week treatment period in the HOE901-U300group and in the Lantus group. Notably, this target range was tighter ascompared with the ADA recommendation of 70-180 mg/dL (3.9-10.0 mmol/L).

In both treatment groups, the percent time spent above upper limit ofglycemic range was higher (57%-58%) than the percent time spent belowlower limit of target range (10-11%).

Overall, the percentage of patients with at least one event regardlessof the category of hypoglycemia, during study was comparable in bothtreatment groups (HOE901-U300, Lantus) and for both injection times(morning or evening). The numerical trends in favor of the HOE901-U300group for nocturnal hypoglycemia have to be interpreted with cautionbecause of the small number of patients.

HOE901-U300 and Lantus, administered either in the morning or in theevening, were well tolerated during the study period, and no specificsafety concerns were observed.

EXAMPLE 5: AN INVESTIGATIONAL NEW INSULIN U300: GLUCOSE CONTROL ANDHYPOGLYCEMIA IN TYPE 2 DIABETES WITH BASAL INSULIN (EDITION II)

Aims:

An investigational new insulin U300 with an even flatter and moreprolonged PK/PD profile than insulin glargine 100 U/mL (U100) is inclinical development. The phase 3 EDITION II study compared the efficacyand safety of U300 versus U100 in people with T2DM using a basal-insulinregimen in combination with OAD.

Methods:

In this multicenter, open-label, 6-month study, participants wererandomized (1:1) to U300 or U100 once daily in the evening. Insulin dosewas titrated to a target fasting plasma glucose (FPG) of 80-100 mg/dL.The primary endpoint was change in HbA_(1c) from baseline to 6 monthsand the 1^(st) main secondary efficacy endpoint in a hierarchicalanalysis was the percentage of participants with severe or confirmed(≤70 mg/dL) nocturnal (2400-0559 h) hypoglycemic event from week 9 tomonth 6.

Results:

811 participants were randomised [mean age 58.2 (SD 9.2) yr, duration ofdiabetes 12.6 (7.0) yr, BMI 34.8 (6.4) kg/m², basal insulin dose 0.67(0.24) U/kg]. Baseline HbA_(1c) was comparable between groups; U300:8.26 (0.86) % vs U100: 8.22 (0.77) %. U300 was non-inferior to U100 forchange in HbA_(1c) [LS mean change −0.57 (SE: 0.09) % and −0.56 (SE:0.09) %, respectively at 6 months; difference −0.01 (95% CI: −0.14 to+0.12) %]. No relevant differences were seen for FPG, 8-pointself-monitored plasma glucose profiles and pre-injection plasma glucose.The percentage of participants with severe or confirmed nocturnalhypoglycemia was significantly lower with U300 vs U100 from week 9 tomonth 6 [21.6% vs 27.9%; relative risk (RR) 0.77 (95% CI: 0.61 to 0.99);p=0.038]. Over the 6-month treatment period, the incidence of anynocturnal hypoglycemia (% of participants with event) was lower withU300 vs U100 [30.5% vs 41.6%; RR 0.73 (95% CI: 0.60 to 0.89)] as was theincidence of any hypoglycemic event at any time of the day (24 h) [U30071.5%; U100 79.3%; RR 0.90 (95% CI: 0.84 to 0.97)]. Severe hypoglycemiaat any time of day was reported by 1.0% of U300 and 1.5% of U100participants. No between-treatment differences in serious adverse eventswere seen.

Conclusion:

In people with T2DM using a basal-insulin regimen with OAD, U300 waswell tolerated and as effective as U100 in blood glucose control. U300was associated with 23% reduction in severe or confirmed nocturnalhypoglycemia from week 9 to month 6 compared with U100 and with a lowerincidence of any nocturnal hypoglycemia event and hypoglycemia at anytime of the day (24 h) over the entire 6-month study duration.

EXAMPLE 6: 6-MONTH, MULTICENTER, RANDOMIZED, OPEN-LABEL, PARALLEL-GROUPSTUDY COMPARING THE EFFICACY AND SAFETY OF A NEW FORMULATION OF INSULINGLARGINE AND LANTUS BOTH IN COMBINATION WITH ORAL ANTIHYPERGLYCEMICDRUG(S) IN PATIENTS WITH TYPE 2 DIABETES MELLITUS WITH A 6-MONTH SAFETYEXTENSION PERIOD—ADMINISTRATION SUB-STUDY COMPARING ADAPTABLE DOSINGINTERVALS WITH FIXED DOSING INTERVALS

1 Synopsis

Phase of Development:

Substudy to phase 3 main study

Objectives:

Primary Objective:

To compare the efficacy of HOE901-U300 injected once daily every 24hours and HOE901-U300 injected once daily at intervals of 24±3 hours interms of change of HbA1c from month 6 of the main study (=baseline ofsub-study) to month 9 of the main study (=endpoint of sub-study) inpatients with type 2 diabetes mellitus.

Main Secondary Objectives:

To compare the safety of the two injection regimens for HOE901-U300 interms of occurrence of hypoglycemia.

Methodology:

Patients randomized on HOE901-U300 and having received HOE901-U300 inthe 6-month main study period are randomized 1:1 to administerHOE901-U300 once daily either every 24 hours (fixed dosing intervals) orevery 24±3 hours (adaptable dosing intervals).

Patients on HOE901-U300 completing the 6-month main study period andmeeting the eligibility criteria for the sub-study were eligible for thesub-study. No specific sample size was requested for the primaryanalysis that is descriptive.

Number of patients: Planned: up to 300 (150 pre treatment arm)Randomized: 89 Treated: 87 Evaluated: Efficacy: 86 Safety: 87

Diagnosis and Criteria for Inclusion:

Inclusion Criteria:

Completion of the 6-month study period in main study (Visit 10),Randomized and treated with HOE901-U300 during the 6-month treatmentperiod (Baseline—month 6), Signed written informed consent for sub-studyobtained.

Key Exclusion Criteria:

Patient not willing to use the adaptable injection intervals of 24±3hours on at least two days per week; In the investigator's opinion, notable to comply with an adaptable dosing schedule; Health condition whichprecludes further participation of the patient in the study.

Study Treatments

Investigational Medicinal Product:

Tested drug: HOE901-U300

Formulation:

HOE901-U300 (insulin glargine 300 U/mL solution) is a sterile,non-pyrogenic, clear, colorless solution in a glass cartridge assembledin a pen-injector (prefilled, disposable pen).

Route of Administration:

subcutaneous injection

Tested Regimen:

Adaptable dosing intervals: HOE901-U300 administered once daily every24±3 hours.

The injection time may have been adapted according to individual needsby up to 3 hours earlier or later than the daily reference injectiontime in the evening fixed at the start of the main study. The maximumintervals, ie, 3 hours earlier or 3 hours later than the fixed dailyreference injection time was to be used on at least 2 days of the weekat the patients' choice. The injection time fixed at start of the mainstudy was to be maintained as reference time for the variation.

Control Regimen:

Fixed dosing intervals: HOE901-U300, once daily injection every 24hours.

Patients continued to inject HOE901-U300 once daily every 24 hours atthe injection time fixed at start of the main study.

Dose:

The dose of HOE901-U300 was to be titrated as needed to achieve ormaintain fasting plasma glucose in the target range of 80 to 100 mg/dL(4.4 mmol/L to 5.6 mmol/L) without hypoglycemia. Changes in the insulindose were based on fasting self-monitored capillary plasma glucose(SMPG) measurements.

Non-Investigational Medicinal Products:

Patients in both treatment regimens were to continue their oralantihyperglycemic background therapy during participation in thesub-study. Doses were to be kept stable throughout the study unlessthere was a specific safety issue related to these treatments. No otherconcomitant anti-diabetic treatments were to be used in this study.

Short term use (ie, 10 days at maximum) of short-acting insulin therapy(eg, due to acute illness or surgery) was not considered as rescuetherapy. Rescue medication was considered as Non-investigationalMedicinal Product.

Duration of Treatment:

The sub-study consisted of a 3 month comparative efficacy and safetytreatment period starting at completion of the 6-month main study periodand ending at completion of Month 9 of the main study.

After completion, patients on the adaptable dosing arm may havecontinued this regimen up to the end of the main study (Month 12).Patients injecting HOE901-U300 every 24 hours continued with theirtreatment regimen up to the end of the main study.

Duration of Observation:

The analysis period for efficacy and safety is the 3-month study periodstarting at Month 6 of the main study and ending at Month 9 of the mainstudy. Results presented in the present KRM refer to this period.

Criteria for Evaluation:

Primary Efficacy Endpoint:

change in HbA_(1c) from baseline (Month 6) to endpoint (Month 9).

Secondary Efficacy Endpoints:

change in FPG (central laboratory) and change in daily dose of basalinsulin, from baseline (Month 6) to endpoint (Month 9).

Safety:

Hypoglycemia (including nocturnal), occurrence of adverse eventsparticularly treatment-emergent adverse events (TEAEs) and seriousadverse events (SAEs), TEAEs leading to withdrawal, injection sitereactions and hypersensitivity reactions. Following information notpresented in KRM: other safety information including vital signs andoverdose.

Statistical Methods:

For this 3-month sub-study, Baseline is defined as Month 6 of the mainstudy; the Endpoint is Month 9 of the main study using last observationcarried forward (LOCF) procedure.

The primary efficacy endpoint (change in HbA_(1c) from baseline [Month6] to endpoint [Month 9]) was analyzed using an analysis of covariance(ANCOVA) model with treatment regimen and country as fixed effects andusing the HbA_(1c) baseline value as a covariate. Differences betweenHOE901-U300 adaptable dosing regimen and HOE901-U300 fixed dosingregimen and two-sided 95% confidence intervals were estimated within theframework of ANCOVA.

All continuous secondary efficacy variables were analyzed using anANCOVA model with treatment regimen and country as fixed effects andusing the corresponding baseline value as a covariate.

Safety analyses were descriptive, based on the safety population.

Summary

Population Characteristics:

A total of 89 patients with type 2 diabetes mellitus were randomized tothe sub-study: 45 patients to the HOE901-U300 adaptable dosing intervalregimen and 44 patients to the HOE901-U300 fixed dosing intervalregimen; 87 patients were exposed to IMP (safety population). The mITTsub-study population (efficacy population) included 86 patients.

A total of 40 (88.9%) patients randomized to HOE901-U300 adaptabledosing intervals and 38 (86.4%) randomized to HOE901-U300 fixed dosingintervals completed the 3-month comparative regimen period. 1 patient(2.2%) randomized to HOE901-U300 adaptable dosing intervals and 2patients (4.5%) randomized to HOE901-U300 fixed dosing intervalsdiscontinued the sub-study prematurely and also discontinued theextension period of the main study.

Demographics and patient characteristics at baseline (Month 6) werewell-balanced between both regimen groups. The mean age of the sub-studypopulation was 57.8 years; 16 of 89 (18.0%) patients were 65 years. 3patients in the adaptable dosing interval regimen and 2 patients in thefixed dosing interval regimen were on insulin or insulin secretagoguestarted as rescue therapy during the main study period. No patient ineither regimen group started rescue therapy during the 3-monthcomparative regimen period.

Compliance to Dosing Interval Regimens:

Compliance to dosing interval regimen was assessed taking into accountthe time interval between 2 consecutive injections and the time intervalbetween an injection and the reference injection time as scheduled atthe main study baseline.

During the sub-study, on average 28.04% of the injections per patient inthe adaptable dosing interval group were taken at the extreme intervalsof <21.5 hours or >26.5 hours between 2 consecutive injections versus2.41% of injections in patients in the fixed dosing interval group,while 88.77% of the injections per patient in the fixed dosing intervalgroup versus 53.09% of the injections per patient in the adaptabledosing interval group were taken within a 23-25 hour interval between 2consecutive injections.

Evaluation of the time intervals between the actual injection and thereference injection times showed a higher percentage of injections perpatient within the 23-25 hour interval in the fixed dosing intervalgroup (mean 65.07%) compared with the adaptable dosing interval group(56.38%). In the adaptable dosing interval group 21.69% injections perpatient were taken at intervals of 21.5-23 hours or at intervals of25-26.5 hours (25.51% in the fixed dosing interval group). These datasuggest that the majority of injections were taken up to 3 hours beforeor after the reference injection time, which was to be fixed as perprotocol in the evening.

Based on the documented injection times during the week preceding thevisits at Month 7.5 and at Month 9, a total of 47.5% of patients in theadaptable dosing group had 4 or more of their injection intervalsoutside the 21.5-26.5 hours interval after previous injection andtherefore were considered to be compliant with the adaptable dosinginterval regimen versus 2.6% of patients in the fixed dosing intervalregimen. In the fixed dosing interval group, in 61.5% of patients allconsecutive injection intervals were within 23-25 hours and thereforepatients can be considered to be compliant with the fixed dosinginterval regimen.

Efficacy:

Primary Efficacy Endpoint (Month 9):

The LS mean change in HbA_(1c) from baseline (Month 6) to endpoint(Month 9) was similar in the groups of adaptable dosing intervals(−0.12% [95% CI: −0.422 to 0.183]) and fixed dosing intervals (−0.25%[95% CI: −0.574 to 0.072]) with the LS mean difference of 0.13% [95% CI:−0.152 to 0.415].

Secondary Efficacy Endpoints (Month 9):

The LS mean change in FPG from baseline (Month 6) to endpoint (Month 9)was similar in the groups of adaptable dosing intervals (−0.46 mmol/L[95% CI: −1.521 to 0.609]) and fixed dosing intervals (−0.25 mmol/L [95%CI: −1.378 to 0.881]) with the LS mean difference of −0.21 [95% CI:−1.200 to 0.784].

In both dosing interval regimens, the average daily basal insulin doseremained stable during the 3-month comparative regimen period

Safety:

During the 3-month comparative substudy period, hypoglycemia events werereported in 16/44 (36.4%) of patients in the adaptable dosing intervalregimen and 18/43 (41.9%) of patients in the fixed dosing intervalregimen Each category of hypoglycemia event was reported by a comparablepercentage of patients in both regimens. No event of severe hypoglycemiaor severe nocturnal hypoglycemia occurred in either regimen.

The percentages of patients with any TEAE (adaptable dosing intervals9/44 [20.5%]; fixed dosing intervals 11/43 [25.6%]) or with a seriousTEAE (adaptable dosing intervals 2/44 [4.5%]; fixed dosing intervals0/43) were comparable between the regimens.

No TEAEs leading to treatment discontinuationor to death, or linked toinjection site reaction or to hypersensitivity reaction were observed ineither dosing interval regimen during the 3-month substudy period.

Conclusions:

The evaluation of the duration of the injection intervals and the %patients with shorter or longer injection intervals than the regular24-hour period suggests that the majority of patients in both dosinginterval regimen groups followed the injection schedule as randomizedand used either adaptable dosing intervals (HOE901-U300 once daily every24 hours±3 hours on at least 2 days a week) or fixed dosing intervals(HOE901-U300 once daily every 24 hours). This allows a comparison of thetwo dosing interval regimens for efficacy and safety analyses.

The efficacy analyses in terms of HbA1c and FPG change from baseline(Month 6) to endpoint (Month 9) showed comparable results for the twodosing interval regimens.

Overall incidence of hypoglycemia (% of patients with at least oneevent) during the 3-month substudy period was comparable in bothregimens regardless of the category of hypoglycemia.

HOE901-U300 given at either adaptable or fixed dosing intervals was welltolerated during the 3-month comparative substudy period; no specificsafety concerns were observed.

Taken together, the substudy results suggest that occasional adaptationof the injection intervals by up to 3 hours earlier or later than thereference time for the once daily injection for HOE901-U300 had noeffects on main efficacy (HbA1c) and safety endpoints, particularlyhypoglycemia events, as compared with once daily injections at 24-hourintervals.

2 Results

2.1 Study Patients

2.1.1 Study disposition

TABLE 60 Patient disposition-Randomized sub-study population HOE901-U300Adaptable Dosing HOE901-U300 Fixed Intervals Dosing Intervals (N = 45)(N = 44) Randomized and treated 44 (97.8%) 43 (97.7%) Completed 3-monthcomparative regimen period 40 (88.9%) 38 (86.4%) Rescue intake duringthe 3-month comparative regimen 3 (6.7%) 2 (4.5%) period ^(a)Permanently discontinued the IMP during the 3-month 1 (2.2%) 2 (4.5%)comparative regimen period Subject's request for treatmentdiscontinuation 1 (2.2%) 1 (2.3%) Reason for treatment discontinuationduring the 3- month comparative regimen period Adverse event 0 0 Lack ofefficacy 0 0 Poor compliance to protocol 0 1 (2.3%) Other reasons 1(2.2%) 1 (2.3%) Status at last study contact of patients who permanentlydiscontinued the treatment during the 3-month comparative regimen periodAlive 1 (2.2%) 2 (4.5%) Dead 0 0 Note: percentages are calculated usingthe number of patients randomized as denominator. ^(a) Includes patientswho started rescue therapy during the main 6-month period and continuedduring the 3-month comparative regimen period.

TABLE 61 Sub-study analysis populations HOE901-U300 HOE901- AdaptableU300 Dosing Fixed Dosing Intervals Intervals All Randomized sub-study 45(100%)  44 (100%)  89 (100%)  population Efficacy sub-study populationsModified Intent-to- 44 (97.8%) 42 (95.5%) 86 (96.6%) Treat (mITT)Sub-study completers 40 (88.9%) 38 (86.4%) 78 (87.6%) Safety sub-study44 43 87 population Note: patients are tabulated according to theirrandomized treatment.

2.1.2 Demographics and Baseline Characteristics

TABLE 62 Demographics and patient characteristics at baseline-Randomized sub-study population HOE901- HOE901- U300 U300 AdaptableFixed Dosing Dosing Intervals Intervals All (N = 45) (N = 44) (N = 89)Age (years) Number 45 44 89 Mean (SD) 58.4 (8.2) 57.2 (10.0) 57.8 (9.1)Median 59.0 57.0 58.0 Min:Max 27:72 33:84 27:84 Age Group (years) [n(%)] Number 45 44 89 <65 36 (80.0%) 37 (84.1%) 73 (82.0%) [65-75[ 9(20.0%) 6 (13.6%) 15 (16.9%) ≥75 0 1 (2.3%) 1 (1.1%) Gender [n (%)]Number 45 44 89 Male 22 (48.9%) 22 (50.0%) 44 (49.4%) Female 23 (51.1%)22 (50.0%) 45 (50.6%) Race [n (%)] Number 45 44 89 Caucasian/White 42(93.3%) 40 (90.9%) 82 (92.1%) Black 3 (6.7%) 3 (6.8%) 6 (6.7%)Asian/Oriental 0 0 0 Other 0 1 (2.3%) 1 (1.1%) Ethnicity [n (%)] Number45 44 89 Hispanic 5 (11.1%) 7 (15.9%) 12 (13.5%) Not Hispanic 40 (88.9%)37 (84.1%) 77 (86.5%) World region [n (%)] Number 45 44 89 North America22 (48.9%) 29 (65.9%) 51 (57.3%) Western Europe 3 (6.7%) 1 (2.3%) 4(4.5%) Eastern Europe 20 (44.4%) 13 (29.5%) 33 (37.1%) Rest of the world0 1 (2.3%) 1 (1.1%) Age is assessed at main study baseline.

TABLE 63 Baseline (Month 6) efficacy data related to dosing interval-Randomized sub-study population HOE901- HOE901- U300 U300 AdaptableFixed Dosing Dosing Intervals Intervals All (N = 45) (N = 44) (N = 89)Average injection time between 2 consecutive injections (hours) Number41 40 81 Mean (SD) 23.98 (0.13) 23.99 (0.12) 23.99 (0.13) Median 24.0024.00 24.00 Q1:Q3 24.00:24.00 24.00:24.02 24.00:24.01 Min:Max 23.2:24.123.3:24.2 23.2:24.2 Average injection time from reference injection(hours) Number 42 41 83 Mean (SD) 24.13 (0.58) 24.20 (1.32) 24.16 (1.01)Median 24.00 24.00 24.00 Q1:Q3 24.00:24.50 23.98:24.38 24.00:24.49Min:Max 22.6:25.6 20.2:28.7 20.2:28.7 Average: mean interval value overat least 3 times intervals during the last 7 days preceding month 6.

2.1.3 Compliance to Dosing Interval Regimen

TABLE 64 Compliance-Dosing interval regimen compliance during the3-month comparative regimen period-Percentage of injections per patientby dosing interval category (time between 2 consecutiveinjections)-Safety sub-study population HOE901-U300 HOE901-U300Adaptable Dosing Fixed Dosing Intervals Intervals % of injections bypatient (N = 44) (N = 43) <21.5 hours or >26.5 hours Number 40 38 Mean(SD) 28.04 (24.38) 2.41 (8.86) Median 28.64 0.00 Q1:Q3 0.00:52.270.00:0.00 Min:Max 0.0:75.0  0.0:50.0 [23-25] hours Number 40 38 Mean(SD) 53.09 (27.19) 88.77 (20.54) Median 47.73 100.00 Q1:Q3 33.33:75.00 83.33:100.00 Min:Max  8.3:100.0  16.7:100.0 [21.5-23[ hours or]25-26.5] hours Number 40 38 Mean (SD) 18.86 (20.88)  8.81 (17.13)Median 9.09 0.00 Q1:Q3  0.00:33.33 0.00:8.33 Min:Max  0.0:66.7  0.0:80.0Note: Percentage of injections (time between 2 consecutive injections)in each dosing interval category is calculated for each patient usingall injection intervals obtained during the last 7 days values beforeMonth 7.5 and Month 9 visits. Note: Only patients with at least 3 timeintervals during the last 7 days values before Month 7.5 or Month 9visits are considered for this table.

TABLE 65 Compliance-Dosing interval regimen compliance during the3-month comparative regimen period-Number (%) patients by injectioninterval between 2 consecutive injections-Safety sub-study populationHOE901-U300 H0E901-U300 Adaptable Dosing Fixed Dosing IntervalsIntervals Number (%) of patients with (N = 44) (N = 43) ≥12 injectionintervals in the  4/40 (10.0%) 17/39 (43.6%) range of [23-25] hours 100%of injection intervals  6/40 (15.0%) 24/39 (61.5%) in the range of[23-25] hours ≥4 injection intervals > 25 27/40 (67.5%)  5/39 (12.8%)hours or <23 hours ≥4 injection intervals > 25 hours 18/40 (45.0%) 1/39(2.6%) ≥4 injection intervals < 23 hours 13/40 (32.5%) 1/39 (2.6%) ≥4injection intervals > 26.5 hours 19/40 (47.5%) 1/39 (2.6%) or <21.5hours ≥4 injection intervals > 26.5 hours  7/40 (17.5%) 0/39 ≥4injection intervals < 21.5 hours 3/40 (7.5%) 1/39 (2.6%) Note: Number ofinjections (time between 2 consecutive injections) is calculated usingall injection intervals (maximum 12) obtained during the last 7 daysvalues before Month 7.5 and Month 9 visits.

TABLE 66 Compliance-Dosing interval regimen compliance during the3-month comparative regimen period-Percentage of injections (time fromreference injection) by dosing interval category-Safety sub-studypopulation HOE901-U300 HOE901-U300 Adaptable Dosing Fixed DosingIntervals Intervals % of injections by patient (N = 44) (N = 43) <21.5hours or >26.5 hours Number 40 39 Mean (SD) 21.93 (21.45)  9.42 (26.43)Median 28.57 0.00 Q1:Q3  0.00:28.57 0.00:0.00 Min:Max  0.0:100.0 0.0:100.0 [23-25] hours Number 40 39 Mean (SD) 56.38 (28.41) 65.07(39.62) Median 64.29 85.71 Q1:Q3 40.66:71.43  28.57:100.00 Min:Max 0.0:100.0  0.0:100.0 [21.5-23[ hours or ]25-26.5] hours Number 40 39Mean (SD) 21.69 (23.29) 25.51 (34.30) Median 14.84 7.14 Q1:Q3 0.00:35.71  0.00:50.00 Min:Max  0.0:100.0  0.0:100.0 Note: Percentageof injections (time from reference injection chosen at the start of themain study) in each dosing interval category is calculated for eachpatient using all injection intervals obtained during the last 7 daysvalues before Month 7.5 and Month 9 visits. Note: Only patients with atleast 3 time intervals during the last 7 days values before Month 7.5 orMonth 9 visits are considered for this table.

2.2 Efficacy Evaluation

2.2.1 Primary Efficacy Endpoint

TABLE 67 Main efficacy analysis-Mean change in HbA1c (%) from baseline(month 6) to Month 9 endpoint using LOCF procedure-mITT sub-studypopulation HOE901-U300 HOE901-U300 Adaptable Dosing Fixed DosingIntervals Intervals HbA1c (%) (N = 44) (N = 42) Baseline (month 6)Number 40 37 Mean (SD) 7.41 (0.96) 7.47 (1.05) Median 7.35 7.30 Min:Max5.8:9.1  5.9:10.3 Month 9 endpoint (LOCF) Number 40 37 Mean (SD) 7.47(0.87) 7.49 (1.11) Median 7.35 7.30 Min:Max 6.0:9.1  5.8:10.0 Changefrom baseline to Month 9 endpoint (LOCF) Number 40 37 Mean (SD) 0.06(0.64) 0.02 (0.63) Median 0.00 −0.10 Min:Max −1.3:1.7   −1.3:1.5   LSMean (SE) ^(a) −0.12 (0.151) −0.25 (0.162) 95% CI (−0.422 to 0.183)(−0.574 to 0.072) LS Mean difference (SE) vs. HOE901-U300 Fixed DosingIntervals ^(a) 0.13 (0.142) 95% CI (−0.152 to 0.415) LOCF = Lastobservation carried forward. ^(a) Analysis of covariance (ANCOVA) modelwith treatment regimen and country as fixed effects and baseline HbA1cvalue as a covariate. Note: For all patients rescued during the 3-monthcomparative regimen period, the last postbaseline HbA1c measurementbefore rescue and during sub-study 3-month on-treatment period will beused as the HbA1c endpoint.

FIG. 14 describes the mean HbA1c (%) by visit during the 3-monthcomparative regimen period—mITT sub-study population.

2.2.2 Secondary Endpoints

2.2.2.1 Fasting Plasma Glucose

TABLE 68 Mean change in FPG (mmol/L) from baseline (month 6) to Month 9endpoint using LOCF procedure-mITT sub-study population HOE901-U300HOE901-U309 Adaptable Dosing Fixed Dosing Intervals Intervals FPG(mmol/L) (N = 44) (N = 42) Baseline (month 6) Number 39 38 Mean (SD)7.08 (1.83) 7.13 (2.71) Median 7.00 6.45 Min:Max 3.7:9.9  3.3:13.8 Month9 endpoint (LOCF) Number 39 38 Mean (SD) 7.38 (2.30) 7.44 (2.16) Median7.10 7.25 Min:Max  3.3:11.7  4.1:12.5 Change from baseline to Month 9endpoint (LOCF) Number 39 38 Mean (SD) 0.30 (2.44) 0.31 (2.62) Median0.10 0.30 Min:Max −3.7:5.9   −6.7:5.5   LS Mean (SE) ^(a) −0.46 (0.534)−0.25 (0.566) 95% CI (−1.521 to 0.609) (−1.378 to 0.881) LS Meandifference (SE) vs. HOE901-U300 Fixed Dosing Intervals ^(a) −0.21(0.497) 95% CI (−1.200 to 0.784) FPG = Fasting Plasma Glucose. LOCF =Last observation carried forward. ^(a) Analysis of covariance (ANCOVA)model with treatment regimen and country as fixed effects and baselineFPG value as a covariate. Note: For all patients rescued during the3-month comparative regimen period, the last postbaseline FPGmeasurement before rescue and during sub-study 3-month on-treatmentperiod will be used as the FPG endpoint.

2.2.2.2 Basal Insulin Dose

FIG. 15 describes the average daily basal (glargine) insulin dose (U) byvisit during the 3-month comparative regimen period—mITT sub-studypopulation.

2.3 Safety Evaluation

2.3.1 Extent of Exposure

TABLE 69 Exposure to investigational product during the 3-monthcomparative regimen period-Safety sub-study population HOE901-U300HOE901-U300 Adaptable Dosing Fixed Dosing Intervals Intervals (N = 44)(N = 43) Cumulative exposure to 10.98 10.40 the sub-study 3-monthtreatment (patient years) Duration of the sub-study 3-month treatment(days) Number 44 42 Mean (SD) 91.2 (4.8) 90.4 (10.7) Median 92.0 92.0Min:Max 76:104 42:117 Duration of the sub-study 3-month treatment bycategory [n (%)] Missing duration 0 1 (2.3%) up to 6 weeks 0 1 (2.3%) >6to 12 weeks 3 (6.8%) 3 (7.0%) >12 weeks 41 (93.2%) 38 (88.4%) Cumulativeduration of the sub-study 3-month treatment by category [n (%)] Missingduration 0 1 (2.3%)  ≥1 days 44 (100%) 42 (97.7%)  >6 weeks 44 (100%) 41(95.3%) >12 weeks 41 (93.2%) 38 (88.4%)

2.3.2 Hypoglycemia

TABLE 70 Number (%) of patients with at least one hypoglycemia eventduring the 3-month comparative regimen period-Safety sub-studypopulation Nocturnal hypoglycemia All hypoglycemia (00:00-05:59)HOE901-U300 HOE901-U300 HOE901-U300 HOE901-U300 Adaptable Dosing FixedDosing Adaptable Dosing Fixed Dosing Type of hypoglycemia IntervalsIntervals Intervals Intervals event n (%) (N = 44) (N = 43) (N = 44) (N= 43) Any hypoglycemia event 16 (36.4%) 18 (41.9%) 7 (15.9%) 10 (23.3%)Severe hypoglycemia 0 0 0 0 Documented symptomatic hypoglycemia ≤3.9mmol/L (70 mg/dL) 10 (22.7%) 14 (32.6%) 5 (11.4%) 7 (16.3%) <3.0 mmol/L(54 mg/dL) 4 (9.1%) 5 (11.6%) 4 (9.1%) 2 (4.7%) Asymptomatichypoglycemia ≤3.9 mmol/L (70 mg/dL) 11 (25.0%) 9 (20.9%) 3 (6.8%) 4(9.3%) <3.0 mmol/L (54 mg/dL) 1 (2.3%) 0 0 0 Probable symptomatic 1(2.3%) 2 (4.7%) 0 0 hypoglycemia Relative hypoglycemia >3.9 mmol/L (70mg/dL) 0 2 (4.7%) 0 0 Severe and/or confirmed^(a) hypoglycemia ≤3.9mmol/L (70 mg/dL) 16 (36.4%) 18 (41.9%) 7 (15.9%) 10 (23.3%) <3.0 mmol/L(54 mg/dL) 4 (9.1%) 5 (11.6%) 4 (9.1%) 2 (4.7%) n (%) = number andpercentage of patients with at least one hypoglycemia event. ^(a)Severeand/or confirmed hypoglycemia = severe and/or confirmed by plasmaglucose ≤3.9 mmol/L (70 mg/dL) (resp. <3.0 mmol/L (54 mg/dL)). Note: Allhypoglycemia events with missing time are counted in the column “Allhypoglycemia”, but not classified as “nocturnal” or “daytime”.

2.3.3 Treatment-Emergent Adverse Events

TABLE 71 Treatment emergent adverse events during the 3-monthcomparative regimen period-Safety sub-study population HOE901-U300HOE901-U300 Adaptable Dosing Fixed Dosing Intervals Intervals n ( %) (N= 44) (N = 43) Patients with any TEAE 9 (20.5%) 11 (25.6%) Patients withany treatment 2 (4.5%)  0 emergent SAE Patients with any TEAE 0 0leading to death Patients with any TEAE 0 0 leading to permanenttreatment discontinuation TEAE: Treatment emergent adverse event, SAE:Serious Adverse Event. n (%) = number and percentage of patients with atleast one TEAE.

TABLE 72 Number (%) of patients with TEAE(s) by primary SOC, HLGT, HLTand PT events during the 3-month comparative regimen period-Safetysub-study population PRIMARY SYSTEM ORGAN CLASS HOE901-U300 HOE901-U300HLGT: High Level Group Term Adaptable Dosing Fixed Dosing HLT: HighLevel Term Intervals Intervals Preferred Term n (%) (N = 44) (N = 43)Any class 9 (20.5%) 11 (25.6%) INFECTIONS AND INFESTATIONS 3 (6.8%)  4(9.3%) HLGT: Infections-pathogen unspecified 2 (4.5%)  4 (9.3%) HLT:Female reproductive tract infections 0 1 (2.3%) Vaginal infection 0 1(2.3%) Vulvovaginitis 0 1 (2.3%) HLT: Lower respiratory tract and lunginfections 0 2 (4.7%) Bronchitis 0 2 (4.7%) HLT: Upper respiratory tractinfections 1 (2.3%)  1 (2.3%) Nasopharyngitis 1 (2.3%)  1 (2.3%) HLT:Urinary tract infections 1 (2.3%)  0 Urinary tract infection 1 (2.3%)  0HLGT: Viral infectious disorders 1 (2.3%)  0 HLT: Influenza viralinfections 1 (2.3%)  0 Influenza 1 (2.3%)  0 METABOLISM AND NUTRITIONDISORDERS 0 1 (2.3%) HLGT: Electrolyte and fluid balance conditions 0 1(2.3%) HLT: Total fluid volume decreased 0 1 (2.3%) Dehydration 0 1(2.3%) NERVOUS SYSTEM DISORDERS 0 3 (7.0%) HLGT: Headaches 0 2 (4.7%)HLT: Headaches NEC 0 2 (4.7%) Headache 0 2 (4.7%) Sinus headache 0 1(2.3%) HLGT: Structural brain disorders 0 1 (2.3%) HLT: Structural braindisorders NEC 0 1 (2.3%) Cerebral atrophy 0 1 (2.3%) EAR AND LABYRINTHDISORDERS 0 2 (4.7%) HLGT: Inner ear and VIIIth cranial nerve disorders0 2 (4.7%) HLT: Inner ear signs and symptoms 0 2 (4.7%) Vertigo 0 2(4.7%) CARDIAC DISORDERS 0 1 (2.3%) HLGT: Cardiac neoplasms 0 1 (2.3%)HLT: Cardiac neoplasms NEC 0 1 (2.3%) Pericardial cyst 0 1 (2.3%) HLGT:Coronary artery disorders 0 1 (2.3%) HLT: Coronary artery disorders NEC0 1 (2.3%) Coronary artery disease 0 1 (2.3%) HLGT: Heart failures 0 1(2.3%) HLT: Heart failures NEC 0 1 (2.3%) Cardiac failure congestive 0 1(2.3%) HLGT: Myocardial disorders 0 1 (2.3%) HLT: Cardiomyopathies 0 1(2.3%) Congestive cardiomyopathy 0 1 (2.3%) VASCULAR DISORDERS 0 2(4.7%) HLGT: Arteriosclerosis, stenosis, vascular 0 1 (2.3%)insufficiency and necrosis HLT: Non-site specific necrosis and vascular0 1 (2.3%) insufficiency NEC Venous stenosis 0 1 (2.3%) HLGT: Vascularhypertensive disorders 0 1 (2.3%) HLT: Vascular hypertensive disordersNEC 0 1 (2.3%) Hypertension 0 1 (2.3%) RESPIRATORY, THORACIC ANDMEDIASTINAL 0 3 (7.0%) DISORDERS HLGT: Respiratory disorders NEC 0 1(2.3%) HLT: Breathing abnormalities 0 1 (2.3%) Dyspnoea 0 1 (2.3%) HLGT:Upper respiratory tract disorders (excl 0 2 (4.7%) infections) HLT:Nasal congestion and inflammations 0 1 (2.3%) Nasal congestion 0 1(2.3%) HLT: Paranasal sinus disorders (excl infections 0 1 (2.3%) andneoplasms) Sinus congestion 0 1 (2.3%) GASTROINTESTINAL DISORDERS 0 1(2.3%) HLGT: Gastrointestinal signs and symptoms 0 1 (2.3%) HLT: Nauseaand vomiting symptoms 0 1 (2.3%) Nausea 0 1 (2.3%) SKIN AND SUBCUTANEOUSTISSUE DISORDERS 1 (2.3%)  1 (2.3%) HLGT: Epidermal and dermalconditions 0 1 (2.3%) HLT: Papulosquamous conditions 0 1 (2.3%) Lichensclerosus 0 1 (2.3%) HLGT: Skin and subcutaneous tissue disorders NEC 1(2.3%)  0 HLT: Skin and subcutaneous tissue ulcerations 1 (2.3%)  0 Skinulcer 1 (2.3%)  0 MUSCULOSKELETAL AND CONNECTIVE 3 (6.8%)  1 (2.3%)TISSUE DISORDERS HLGT: Joint disorders 1 (2.3%)  0 HLT:Osteoarthropathies 1 (2.3%)  0 Spinal osteoarthritis 1 (2.3%)  0 HLGT:Musculoskeletal and connective tissue 1(2.3%)  0 disorders NEC HLT:Musculoskeletal and connective tissue pain 1 (2.3%)  0 and discomfortPain in extremity 1 (2.3%)  0 HLGT: Tendon, ligament and cartilagedisorders 1 (2.3%)  1 (2.3%) HLT: Cartilage disorders 1 (2.3%)  1 (2.3%)Osteochondrosis 1 (2.3%)  1 (2.3%) RENAL AND URINARY DISORDERS 1 (2.3%) 0 HLGT: Urolithiases 1 (2.3%)  0 HLT: Renal lithiasis 1 (2.3%)  0Nephrolithiasis 1 (2.3%)  0 REPRODUCTIVE SYSTEM AND BREAST 1 (2.3%)  0DISORDERS HLGT: Vulvovaginal disorders (excl infections and 1 (2.3%)  0inflammations) HLT: Vulvovaginal disorders NEC 1 (2.3%)  0 Vaginalhaemorrhage 1 (2.3%)  0 GENERAL DISORDERS AND ADMINISTRATION 2 (4.5%)  1(2.3%) SITE CONDITIONS HLGT: General system disorders NEC 2 (4.5%)  1(2.3%) HLT: Asthenic conditions 0 1 (2.3%) Fatigue 0 1 (2.3%) HLT:Oedema NEC 1 (2.3%)  0 Oedema peripheral 1 (2.3%)  0 HLT: Pain anddiscomfort NEC 2 (4.5%)  0 Chest pain 1 (2.3%)  0 Non-cardiac chest pain1 (2.3%)  0 INVESTIGATIONS 0 2 (4.7%) HLGT: Cardiac and vascularinvestigations (excl 0 1 (2.3%) enzyme tests) HLT: Vascular tests NEC(incl blood pressure) 0 1 (2.3%) Blood pressure increased 0 1 (2.3%)HLGT: Physical examination and organ system status 0 1 (2.3%) topicsHLT: Physical examination procedures and organ 0 1 (2.3%) system statusWeight increased 0 1 (2.3%) INJURY, POISONING AND PROCEDURAL 1 (2.3%)  0COMPLICATIONS HLGT: Medication errors 1 (2.3%)  0 HLT: Overdoses 1(2.3%)  0 Accidental overdose 1 (2.3%)  0 SURGICAL AND MEDICALPROCEDURES 0 1 (2.3%) HLGT: Head and neck therapeutic procedures 0 1(2.3%) HLT: Paranasal therapeutic procedures 0 1 (2.3%) Sinus operation0 1 (2.3%) TEAE: Treatment emergent adverse event, SOC: System organclass, HLGT: High level group term, HLT: High level term, PT: Preferredterm. MedDRA 16.0. n (%) = number and percentage of patients with atleast one TEAE. Note: Table sorted by SOC internationally agreed orderand HLGT, HLT, PT by alphabetic order.

2.3.4 Serious Treatment-Emergent Adverse Events

TABLE 73 Number (%) of patients with treatment emergent SAE(s) byPrimary SOC, HLGT, HLT and PT during the 3-month comparative regimenperiod-Safety sub-study population PRIMARY SYSTEM ORGAN CLASSHOE901-U300 HOE901-U300 HLGT: High Level Group Term Adaptable DosingFixed Dosing HLT: High Level Term Intervals Intervals Preferred Term n(%) (N = 44) (N = 43) Any class 2 (4.5%) 0 MUSCULOSKELETAL AND 1 (2.3%)0 CONNECTIVE TISSUE DISORDERS HLGT: Joint disorders 1 (2.3%) 0 HLT:Osteoarthropathies 1 (2.3%) 0 Spinal osteoarthritis 1 (2.3%) 0 GENERALDISORDERS AND 1 (2.3%) 0 ADMINISTRATION SITE CONDITIONS HLGT: Generalsystem 1 (2.3%) 0 disorders NEC HLT: Pain and discomfort NEC 1 (2.3%) 0Chest pain 1 (2.3%) 0 TEAE: Treatment emergent adverse event, SOC:System organ class, HLGT: High level group term, HLT: High level term,PT: Preferred term. MedDRA 16.0. n (%) = number and percentage ofpatients with at least one treatment emergent SAE. Note: Table sorted bySOC internationally agreed order and HLGT, HLT, PT by alphabetic order.

2.3.5 Treatment Emergent Adverse Events Leading to Withdrawal

TABLE 74 Number (%) of patients with TEAE(s) leading to permanenttreatment discontinuation by Primary SOC, HLGT, HLT and PT during the3-month comparative regimen period-Safety sub-study population No dataTEAE: Treatment emergent adverse event, SOC: System organ class, HLGT:High level group term, HLT: High level term, PT: Preferred term. MedDRA16.0. n (%) = number and percentage of patients with at least one TEAEleading to permanent treatment discontinuation. Note: Table sorted bySOC internationally agreed order and HLGT, HLT, PT by alphabetic order.

2.3.6 Other Significant Treatment Emergent Adverse Events

2.3.6.1 Injection Site Reactions

TABLE 75 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term-Injection sitereactions during the 3-month comparative regimen period-Safety sub-studypopulation No data TEAE: Treatment emergent adverse event, PT: Preferredterm. MedDRA 16.0 n (%) = number and percentage of patients with atleast one injection site reactions TEAE. Note: Table sorted bydecreasing frequency of PT in HOE901-U300 adaptable dosing intervalsregimen.

2.3.6.2 Hypersensitivity Reactions

TABLE 76 Number (%) of patients experiencing at least one TEAE byrelevant Standardized MedDRA Queries and Preferred Term-Hypersensitivityreactions during the 3-month comparative regimen period-Safety sub-studypopulation No data TEAE: Treatment emergent adverse event, PT: Preferredterm. MedDRA 16.0 n (%) = number and percentage of patients with atleast one hypersensitivity reactions TEAE. Note: Table sorted bydecreasing frequency of PT in HOE901-U300 adaptable dosing intervalsregimen.

1: A method of treating Type II Diabetes Mellitus in a patient who hasan increased risk of hypoglycemia comprising administering to thepatient an aqueous pharmaceutical formulation comprising 300 U/mL ofinsulin glargine [equimolar to 300 IU human insulin], wherein thetreatment reduces the risk of nocturnal hypoglycemia and wherein thepatient who has an increased risk of hypoglycemia is a diabetes type IIpatient having experienced at least one hypoglycemic event. 2: Themethod of claim 1, wherein the nocturnal hypoglycemia is selected fromsymptomatic hypoglycemia, severe symptomatic hypoglycemia, documentedsymptomatic hypoglycemia, probable symptomatic hypoglycemia, relativesymptomatic hypoglycemia, and asymptomatic hypoglycemia. 3: The methodof claim 1, wherein the time interval between administrations is in therange of 20 hours to 23.5 hours or in the range of 24.5 hours to 28hours. 4: The method of claim 1, wherein the patient to be treated has aHbA1c value of at least 8% at the onset of treatment. 5: The method ofclaim 1, wherein the patient to be treated has a BMI of at least 30kg/m² at the onset of treatment. 6: The method of claim 1, wherein thepatient to be treated received a basal insulin directly prior to thetreatment. 7: The method of claim 1, wherein the patient to be treatedreceived a mealtime short-acting insulin directly prior to thetreatment. 8: The method of claim 1, wherein the formulation isadministered once daily in the evening at a predetermined time. 9: Themethod of claim 1, wherein the patient additionally receives a mealtimeshort-acting insulin. 10: The method of claim 1, wherein the aqueouspharmaceutical formulation comprises one or more excipients selectedfrom the group consisting of zinc, m-cresol, glycerol, polysorbate 20,and sodium. 11: The method of claim 10, wherein the aqueouspharmaceutical formulation comprises 90 μg/mL zinc, 2.7 mg/mL m-cresol,and 20 mg/ml glycerol 85%. 12: The method of claim 10, wherein theaqueous pharmaceutical formulation comprising 90 μg/mL zinc, 2.7 mg/mLm-cresol, 20 μg/mL polysorbate 20 and 20 mg/mL glycerol 85%. 13: Themethod of claim 1, wherein the pH of the aqueous pharmaceuticalformulation is between 3.4 and 4.6. 14: The method of claim 13, whereinthe pH of the aqueous pharmaceutical formulation is
 4. 15: The method ofclaim 1, wherein the Diabetes Mellitus Type II is not adequatelycontrolled with at least one oral antihyperglycemic alone. 16: Themethod of claim 15, wherein the at least one oral antihyperglycemic ismetformin. 17: The method of claim 16, wherein a treatment with at least1.5 g/day of metformin does not adequately control the DiabetesMellitus. 18: The method of claim 17, wherein the aqueous pharmaceuticalformulation is administered in combination with at least one oralantihyperglycemic agent. 19: The method of claim 18, wherein the atleast one antihyperglycemic agent is metformin. 20: The method of claim1, wherein the aqueous pharmaceutical formulation is administered on atleast two days per week. 21: The method of claim 1, wherein the aqueouspharmaceutical formulation is administered on at least three days perweek. 22: The method of claim 1, wherein the aqueous pharmaceuticalformulation is administered on at least four days per week.